SLC22A5 Database

  • Reference sequences were NC_000005.8 and NM_003060.2. cDNA number 1 is the "A" of the start codon.
  • Frameshift is documented by the original amino acid followed by the codon number and "fs" (ex. Leu159 fs).
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  • "Live Search" any term in the search box, such as "exon" , "missense", "benign" , etc...
  • Transport Activity - Assayed in patient cultured fibroblasts (% of normal).
  • Expression - Assayed in chinese hamster ovary cells (CHO) expressing mutant OCTN2 (% of wild type).


271 variants found

Genomic Position Location ▾ Mutation Type Nucleotide Change Protein Change Transport Activity Expression Classification References Comments
Missense p.G152D VUS Calderon et.al unpublished
Hispanic female infant identified with abnormal NBS, had low total and free plasma carnitine, and was heterozygous for p.G152D and p.R289X.
Exon 3 Missense c.631T>C p.Y211H VUS Calderon et.al unpublished
Caucasian hispanic male with abnormal NBS was heterozygous for p.Y211H and p.R257W (and homozygous for polymorphisms c.285T>C, c.652+6A>G, c.807A>G). Patient had low plasma total and free carnitine.
5'UTR c.-207G>C Benign Peltekova (2004)
Polymorphism within the promoter region shown to reduce expression of the protein by two-fold. This polymorphism is thought to be associated with Crohns disease. Grube et. al (2006, Circulation 113: 1114-1122) reported this polymorphism was associated with increased expression of OCTN2 following administration of beta-blockers.
5'UTR c.-185A>C 33 Uncertain Calderon et.al unpublished
Detected in two samples at our laboratory with c.-149G>A. One of the samples also had p.V151V and transport activity in fibroblasts at 7.7.
5'UTR c.-149G>A 33 Uncertain Calderon et.al unpublished
Detected in two samples at our laboratory with c.-185A>C. One of the samples also had p.V151V and transport activity in fibroblasts at 7.7.
5'UTR Deletion c.-91_22del Pathogenic Nezu (1999)
Two siblings were homozygous for this 113 bp deletion (parents and asymptomatic siblings were heterozygous). Two additional siblings died within six months after birth (genotype was not tested).
5'UTR c.-78C>T 33 Benign Koizumi (1999)
This variant was found in in a haplotype with c.-77G>A in control individuals with normal serum free-carnitine measurements (allele frequency = 32%). Additionally, p.W132X was found in linkage disequilibrium with this haplotype in individuals with low free-serum carnitine.
5'UTR c.-77G>A 33 Benign Koizumi (1999)
This variant was found in in a haplotype with c.-78G>A in control individuals with normal serum free-carnitine measurements (allele frequency = 32%). Additionally, p.W132X was found in linkage disequilibrium with this haplotype in individuals with low free-serum carnitine.
5'UTR c.-38A>C Benign Calderon et.al unpublished
All of the samples (patient and controls) tested at our laboratory were homozygous C at this position.
Exon 1 Missense c.3G>T p.M1I <5 Likely Pathogenic Dobrowolski (2005)
Chinese patient was heterozygous for this mutation and p.R282X.
Exon 1 Insertion c.4_5insC p.R2PfsX136 Pathogenic Nezu (1999)
Patient is compound heterozygous for this mutation and p.W132X
Exon 1 Nonsense c.12C>G p.Y4X <1 Pathogenic Wang (2001)
Pakistani patient was homozygous for this mutation. Grandparents on one side of the family were siblings and on the other side are also related. Sibling of patient died at 7 months of age with SCD presentations and other two siblings are carriers.
Exon 1-8 Deletion c.33_1427del p.G12_L477del 2 Pathogenic Lamhonwah (1998)
Large deletion found in two patients. Patient 1 of Italian descent was heterozygous for this mutation and p.G218VfsX68. Patient 2 of Mexican descent was heterozygous for this mutation and p.T219SfsX20.
Exon 1 Missense c.34G>A p.G12S VUS Calderon et.al unpublished
Caucasian adult male with no clinical presentations was heterozygous for this variant (sibling was affected with PCD).
Exon 1 Missense c.34G>A p.G12S VUS Calderon et.al unpublished
Caucasian female with abnormal NBS, low total/free plasma carnitine and normal carnitine excretion in urine, was heterozygous for p.G12S, p.R82R and p.I89fs (c.265_266insGGCTCGCCACC).
Exon 1 Missense c.34G>A p.G12S VUS Li (2010)
5 yr. old male presenting with 'sids-like episode' was heterozygous for p.g12s. This variant is predicted to be pathogenic by polyphen and sift (computer based algorithms).
Exon 1 Missense c.34G>A p.G12S VUS Calderon et.al unpublished
Caucasian female with abnormal NBS was heterozygous for p.G12S and p.V151V. Patient had low plasma total and free carnitine and high urine excretion of carnitine.
Exon 1 Missense c.34G>A p.G12S VUS Calderon et.al unpublished
Caucasian adult male was heterozygous for this variation. Patient presented with cardiomegaly, autonomic and peripheral neuropathy, orthostatic hypotension. Patient was tested for plasma carnitine levels three separate times and presented with low to normal levels (unsure if patient was receiving carnitine supplementation).
Exon 1 Missense c.43G>T p.G15W 3 Pathogenic Calderon et.al unpublished
Detected in a patient sample with p.R83L.
Exon 1 Missense c.43G>T p.G15W Pathogenic El-Hattab (2010)
Indian female identified due to infant having abnormal NBS. This mother was homozygous for p.G15W and had low plasma total, free, and acyl-carnitine. This mutation was not detected in the child.
Exon 1 Missense c.43G>T p.G15W Pathogenic Calderon et.al unpublished
Caucasian male with abnormal NBS was homozygous for p.G15W and presented with Normal Plasma free and low total carnitine levels, high urine carnitine free and total.
Exon 1 Missense c.43G>T p.G15W Pathogenic Calderon et.al unpublished
Asian male infant with abnormal NBS was heterozygous for p.G15W and p.R83L (and homozygous for common polymorphisms c.285T>C, c.652+6A>G, c.807A>G). Patient presented with low plasma carnitine.
Exon 1 Deletion c.43delG p.G15Gfs*28 Pathogenic Carducci (unpublished)
Italian patient had abnormal NBS and was compound heterozygous for p.G15Gfs*28, Intron 1 c.394-16T>A, and Exon 9 p.L498Q.
Exon 1 Missense c.51C>G p.F17L 14 18 Pathogenic Calderon et.al unpublished
Newborn female with abnormal NBS was heterozygous for p.F17L inherited from mom.
Exon 1 Missense c.51C>G p.F17L Pathogenic Calderon et.al unpublished
Newborn male with abnormal NBS was homozygous for p.F17L and a suspected benign variant in Exon 4 (c.824+38G>T). Patient was homozygous for common polymorphisms (c.285T>C, c.652+6 A>G, and c.807A>G) and had low plasma carnitine.
Exon 1 Missense c.56G>C p.R19P <5 4 Pathogenic Wang (2001)
Italian patient was heterozygous for this mutation and an 11 bp duplication in exon 1 resulting in p.I89GfsX45.
Exon 1 Missense c.56G>C p.R19P Pathogenic Calderon et.al unpublished
Caucasian adult male was heterozygous for p.R19P, and had low plasma free and total carnitine. Child had abnormal NBS.
Exon 1 Missense c.56G>C p.R19P Pathogenic Calderon et.al unpublished
Female identified with child having abnormal NBS was heterozygous for p.R19P. Patient had low plasma free and total carnitine and normal carnitine output in urine.
Exon 1 Missense c.59T>A p.L20H VUS Calderon et.al unpublished
African American female with abnormal NBS was heterozygous for his variant and the polymorphisms c.-77G>A, c.-78C>T, c.652+6A>G (homozygous).
Exon 1 Deletion c.67_69delTTC p.F23del 2 Pathogenic Lamhonwah (2002)
This deletion was also found in an affected male patient and sister. Patient also carried c.632A>G, p.Y211C. Sibling was tested for familial mutations only.
Exon 1 Missense c.83G>T p.S28I <12 Likely Pathogenic Rahbeeni (2002)
Patient from Saudi Arabia was homozygous for this mutation.
Exon 1 Missense c.95A>G p.N32S 21 0.4 Pathogenic Lamhonwah (2002)
Two patients of Danish descent were reported to be homozygous for N32S (Christensen et al. 2000; Journal of Inherited Metabolic Disease 23 (Supplement 1): p.117 abstract only). Also detected with P46S (both heterozygous) in a patient with arrhythmias and transport activity of 5% of normal (Schimmenti et al. 2007, Molecular Genetics and Metabolism 90 (4): 441-445)
Exon 1 Missense c.95A>G p.N32S Pathogenic Calderon et.al unpublished
Caucasian adult female identified with child having abnormal NBS was heterozygous for p.N32S and p.G12S. Patient had low plasma carnitine.
Exon 1 Missense c.95A>G p.N32S Pathogenic Calderon et.al unpublished
Caucasian infant female identified with abnormal NBS was heterozygous for this mutation and p.[A142S;R488H]. Patient had low free and total plasma carnitine and normal urine output.
Exon 1 Missense c.34G>A p.G12S VUS Calderon et.al unpublished
Caucasian adult female identified with child having abnormal NBS was heterozygous for p.N32S and p.G12S. Patient had low plasma carnitine.
Exon 1 Missense c.131C>T p.A44V VUS Calderon et.al unpublished
Caucasian adult female was heterozygous for p.A44V and p.[A142S,R488H]; and homozygous for common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G, c.824+13C>T).
Exon 1 Missense c.136C>T p.P46S <5 <5 Pathogenic Schimmenti (2007)
Identified in two mothers via newborn screening. Patient 1 was heterozygous for mutation and p.R282X. Patient 2 was heterozygous for mutation and p.I521HX3. Additional three cases reported in house, each detected with one of the following mutations: p.T232M, p.P398L, p.V151M. This mutation was also detected in two African American brothers, and an unrelated female patient, with p.A142S and p.R488H.
Exon 1 Missense c.136C>G p.P46S 6 Pathogenic Calderon et.al unpublished
Caucasian female was heterozygous for P.T232M and p.P46S and carnitine transport activity in patient's fibroblasts was <6% or normal control. Patient had low plasma free and total carnitine levels.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian adult female identified through child having abnormal NBS. Patient had low free and total plasma carnitine and normal urine carnitine levels before supplementation (high levels after supplementation).This patient was heterozygous for p.P46S.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian adult female identified through child having abnormal NBS presented with fatigue and low free and total plasma carnitine. This mother was heterozygous for p.P46S and c.1078_1083dupGGGCTT.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Asymptomatic female with abnormal NBS was heterozygous for p.R254Q and P46S. Patient had low free and total plasma carnitine, normal urine free carnitine, and low urine total carnitine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Asymptomatic Caucasian female was heterozygous for p. P46S. Patient had low free and total plasma carnitine, normal urine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian male with abnormal NBS was heterozygous for p.P46S and had low plasma free and total carnitine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Female patient identified with abnormal NBS was herozygous for p.P46S and had low plasma free and total carnitine levels.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian adult female identified with child having abnormal NBS was heterozygous for p.P46S and p.R254Q. Clinical presentations included low plasma free and total carnitine and normal free, low total carnitine excretion in urine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian female identified with abnormal NBS was heterozygous for P.P46S and the silent variant p.V151V. Patient had low plasma free and total carnitine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian female identified with abnormal NBS was homozygous for this mutation. Patient was homozygous for commong polymorphisms (c.285T>C, c.652+6A>G, c.807A>G) and had low plasma carnitine and high urine excretion of carnitine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian adult female presenting with headaches and fatigue was heterozygous for p.P46S. Patient had low free and total plasma carnitine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian adult female was heterozygous for p.P46S and p.P455R; and homozygous for polymorphisms (c.285T>C,c.652+6A>G, c.807A>G). Patient had low total.free plasma carnitine and normal carnitine in urine.
Exon 1 Missense c.136C>G p.P46S Pathogenic Calderon et.al unpublished
Caucasian male infant with abnormal NBS was heterozygous for p. P46S, p.V175M, and p.S231F. Patient presented with low plasma carnitine and low urine output of carnitine.
Exon 1 Missense c.137C>T p.P46L 7 Likely Pathogenic Calderon et.al unpublished
This mutation was detected in a patient sample with p.L394del (both heterozygous).
Exon 1 Deletion c.148delT p.C50AfsX9 Pathogenic Carducci (unpublished)
Caucasian female of Italian origin identified via newborn screening, was compound heterozygote: c.[-149G>A];[148delT] (confirmed in parents). Patient is asymptomatic at 8 months.
Exon 1 Missense c.196A>C p.T66P VUS Li (2010)
1-month old female identified with abnormal NBS and presented with low free plasma carnitine was heterozygous for p.T66P.
Exon 1 Missense c.196A>C p.T66P VUS Calderon et.al unpublished
Female infant identified with abnormal NBS was heterozygous for p.T66P and p.R399W. Patient had low plasma carnitine and normal urine output of carnitine.
Exon 1 Silent c.207G>C p.L69L Benign Gazouli (2005)
Reported to be associated with Crohns disease.
Exon 1 Missense c.224G>C p.R75P VUS Li (2010)
3-month old female identified with abnormal NBS was heterozygous for p.R75P and p.A142S.
Exon 1 Deletion c.232delC p.H79TfsX51 <1 Pathogenic Amat di San Filippo (2006)
Pakistani patient was homozygous for this mutation. Reported as p.P78fsX129
Exon 1 Silent c.246C>T p.R82R Benign Calderon et.al unpublished
Caucasian female identified with abnormal NBS had a family history of low plasma carnitine levels (mother and maternal grandmother) and was heterozygous for p.R82R and p.I89GfsX45. Patient's free and total plasma carnitine were low even after supplementation.
Exon 1 Missense c.248G>T p.R83L 0 <1 Pathogenic Makhseed (2004)
Patient of unknown ancestry was homozygous for this mutation. Sibling was also homozygous but asymptomatic by age 11. Both children were receiving carnitine supplementation, however, patient was not responsive to treatment. Parents were heterozygous for this mutation. Vegetarian Indian (Asian) patient presenting with fatigue was heterozygous for p.R83L and p.A214V (patient was on carnitine supplementation but plasma carnitine levels were still low and urine carnitine excretion was high after supplementation)
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Pakistani female with abnormal NBS was homozygous for p.R83L (parents were half siblings as grandmothers were identical twins).
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Female patient was homozygous for this mutation and presented with low plasma carnitine.
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Asian/Indian male infant identiied with abnormal NBS was homozygous for p.R83L and common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G). Patient had low free/total plasma carnitine and normal carnitine output in urine.
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Asian female infant identiied with abnormal NBS was heterozygous for p.R83L and p.R227C. Patient had low plasma carnitine.
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Asian male infant identiied with abnormal NBS was homozygous for p.R83L and common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G). Patient had low plasma carnitine and high urine excretion.
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Asian/Indian male infant identiied with abnormal NBS was heterozygous for p.R83L and common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G). Patient had low plasma carnitine and low carnitine output in urine.
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Asian/Indian adult female identiied with child having abnormal NBS was homozygous for p.R83L and common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G). Patient had low plasma carnitine and normal carnitine output in urine.
Exon 1 Missense c.248G>T p.R83L Pathogenic Calderon et.al unpublished
Asian male infant with abnormal NBS was heterozygous for p.G15W and p.R83L (and homozygous for common polymorphisms c.285T>C, c.652+6A>G, c.807A>G). Patient presented with low plasma carnitine.
Exon 1 Insertion c.254_264dupGGCTCGCCACC p.I89GfsX45 <5 Pathogenic Wang (2001)
Swiss patient was homozygous for this mutation and a second unrelated patient of italian descent was heterozygous fot this mutation with p.R19P. Lamhonwah et al. reported another patient of unknown ethnicity was heterozygous for this mutation, p.T468R, and a silent polymorphism p.R82R (c.246CT; Am. Journal of Medical Genetics 111: 271-284) and transport activity <6% of normal activity.
Exon 1 Insertion c.254_264dupGGCTCGCCACC p.I89GfsX45 Pathogenic Calderon et.al unpublished
Identified in-house as c.265_266insGGCTCGCCACC but same as c.254_264dupGGCTCGCCACC first identified by Wang (2001). Caucasian female identified with abnormal NBS had a family history of low plasma carnitine levels (mother and maternal grandmother) and was heterozygous for p.R82R and p.I89GfsX45. Patient's free and total plasma carnitine were low even after supplementation.
Exon 1 Insertion c.254_264dupGGCTCGCCACC p.I89GfsX45 Pathogenic Li (2010)
Identified as c.265_266insGGCTCGCCACC but same as c.254_264dupGGCTCGCCACC first described by Wang (2001). Li et al 2010 identified this mutation in a fifteen month old female with no other variants (patient was identified with abnormal NBS).
Exon 1 Insertion c.265_266insGGCTCGCCACC p.I89GfsX45 Pathogenic Calderon et.al unpublished
Caucasian female with abnormal NBS, low total/free plasma carnitine and normal carnitine excretion in urine, was heterozygous for p.G12S, p.R82R and p.I89fs (c.265_266insGGCTCGCCACC).
Exon 1 Missense c.272A>G p.N91S Uncertain Calderon et.al unpublished
Caucasian Hispanic female identified with abnormal NBS was heterozygous for this variation. Patient had low plasma free and total carnitine and high urine excretion of carnitine.
Exon 1 Missense c.278C>G p.S93W Pathogenic Calderon et.al unpublished
Asian female with abnormal NBS and low total/free plasma carnitine was heterozygous for p.S93W and p.S467C.
Exon 1 Missense c.283C>G p. L95V <2 Pathogenic Calderon et.al unpublished
Burmese female identified with abnormal NBS was homozygous for p.D115G and p.L95V and had low total and free plasma carnitine.
Exon 1 Silent c.285C>T p.L95L Benign Tang (2002)  
Exon 1 Missense c.287G>C p.G96A VUS Calderon et.al unpublished
Patient was heterozygous for this mutation and p.S467C (assumed to be on different chromosomes because child was a carrier of p.S467C). Pt. had low free and total plasma carnitine levels.
Exon 1 Missense c.287G>C p.G96A VUS Li (2010)
15-month female identified with abnormal NBS and presenting with low total and free plasma carnitine was heterozygous for p.G96A.
Exon 1 Silent c.291C>T p.L97L Benign Tang (1999)
Documented as 506 C/T
Exon 1 Missense c.344A>G p.D115G <2 Pathogenic Calderon et.al unpublished
Burmese female identified with abnormal NBS was homozygous for p.D115G and p.L95V and had low total and free plasma carnitine.
Exon 1 Nonsense c.350G>A p.W117X Pathogenic Li (2010)
14-year old male presenting with cardiomyopathy was heterozygous for p.W117X and p.N192IfsX12.
Exon 1 Missense c.364G>T p.D122Y 53 VUS Calderon et.al unpublished
Caucasian male presenting with low free and total plasma carnitine and high urine excretion of carnitine inherited one copy of p.D122Y from mom (tested in our lab). This patient was found to contain a 1.2Mb deletion (13q12.12 including 8 genes; detected in outside lab) detected in father as well. Transport activity in fibroblasts was 53% of normal.
Exon 1 Missense c.364G>T p.D122Y VUS Calderon et.al unpublished
Caucasian female with abnormal NBS, presenting with hypotonia and low plasma carnitine (total and free), was heterozygous for p.D122Y.
Exon 1 Missense c.364G>T p.D122Y VUS Li (2010)
19-year old female presenting with cardiomyopathy and myopathy was heterozygous for p.D122Y. This variant is predicted to be pathogenic by Poly-Phen and SIFT analysis (computer based algorithms).
Exon 1 Missense c.368T>G p.V123G VUS Li (2010)
Li et al. 2010 identified an adult female heterozygous for this VUS (child had an abnormal NBS).
Exon 1 Missense c.368T>G p.V123G VUS Li (2010)
Asymptomatic adult female identified with child having abnormal NBS was heterozygous for p.V123G.
Exon 1 Missense c.393G>C p.E131D 17 VUS Calderon et.al unpublished
Adult male was heterozygous for p.E131D. Patient had low free (22) and total (29) plasma carnitine. Transport activity was 17% of normal.
Intron 1 c.393+17G>A 50 Benign Calderon et.al unpublished
Detected in a carrier sample with p.P46S. c.393+17G>A was also found in an African-American/Caucasian patient with low total/free plasma carnitine and heterozygous for p.L186P, p.P398L and p.P549S. Other benign variants detected were p.L95L (c.285C>T), c.1268-34A>G, and c.1587-38A>C. Another patient of African-American descent was heterozygous for p.P549S, p.W132X, and p.T232M (and likely benign variants c.393+17G>A, c.1268-34A>G and c.1587-38A>C).
IVS 1 c.394-16T>A Benign Carducci (unpublished)
Italian patient had abnormal NBS and was compound heterozygous for p.G15Gfs*28, Intron 1 c.394-16T>A, and Exon 9 p.L498Q.
Exon 2 Nonsense c.396G>A p.W132X <5 Pathogenic Tang (1999)
Chinese patient was heterozygous for this mutation and p.P478L (patient died at 6 months). Koizumi et al. found this mutation in three individuals of Japanese origin (1999, Hum. Molec. Gen. 8 (12):2247-2254). Nezu et al (1999, Nature Genetics 21 (1): 91-94) reported a patient with no functional carnitine transporter heterozygous for this mutation and p.R2PfsX136.
Exon 2 Silent c.414C>T p.D138D 45 Benign Calderon et.al unpublished
Caucasian male was heterozygous for p.D138D and c.1674+47C>T. p.D138D is likely a benign variant.
Exon 2 Missense c.415G>A p.D139N VUS Calderon et.al unpublished
Male patient presenting with irregular heartbeat and low free and total plasma carnitine was heterozygous for p.D139N.
Exon 2 Missense c.424G>T p.A142S 5 45 Pathogenic Amat di San Filippo (2006)
Expression of this mutation alone in CHO cells did not significantly impare carnitine transport, however, carnitine transport was significantly reduced when this mutation was expressed in cis with p.R488H. Caucasian patient was heterozygous for this mutation and p.R488H (inherited from mom), and p.T440M (inherited from dad). Additional Caucasian female with <5 micromoles/L of total free plasma carnitine inherited p.A142S/p.R488H from dad and c.1586+1 G>T from mom. Patient was treated for cardiac arrest and possible cardiomyopathy. Heart function improved with carnitine supplementation. Two African American brothers, and an unrelated Caucasian female, were heterozygous for this mutation, p.R488H and p.P46S. Female patient had one copy each of p.A142S, p.R488H and p.P398L.
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Male patient with abnormal NBS and low free and total plasma carnitine was heterozygous for p.A142S, R488H, S280F and homozygous for benign variants c.285T>C, c.652+6A>G, c.807A>G, c.824+13C>T. Mother also had low free and total plasma carnitine.
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Adult female was heterozygous for p.R488H and p.R289X (homozygous for all common polymorphisms as previous case).
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Caucasian adult female was heterozygous for p.A44V and p.[A142S,R488H]; and homozygous for common polymorphisms.
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Caucasian adult male presenting with fatigue and weakness was heterozygous for p.[A142S, R488H].
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Female patient with abnormal NBS was heterozygous for p.A142S and p.R488H. Patient was fussy and had GI disconfort, and presented with plasma carnitine levels of 17 (F) and 30 (T).
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Caucasian/Native American male with abnormal NBS was heterozygous for p.[A142S; R488H]. Patient had low free/total plasma carnitine.
Exon 2 Missense c.424G>T p.A142S <21 Pathogenic Calderon et.al unpublished
Caucasian adult female was heterozygous fro p.[A142S; R488H] and presented with fatigue. Patient had low free/total plasma carnitine and fibroblast carnitine transport activity was <21% of normal.
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Caucasian infant female identified with abnormal NBS was heterozygous for p.N32S and p.[A142S;R488H]. Patient had low free and total plasma carnitine and normal urine output.
Exon 2 Missense c.424G>T p.A142S Pathogenic Calderon et.al unpublished
Female Caucasian child was heterozygous for p.[A142S;R488H]. Patient presented with low plasma carnitine.
Exon 2 Missense c.428C>T p.P143L Likely Pathogenic Lee NC et al. 2010
2-month old female identified with abnormal NBS, asymptomatic mother and sister were heterozygous for p.P143L (infant and mother had low total and free plasma carnitine, sister had low total plasma carnitine).
Exon 2 Missense c.430C>T p.L144F Benign Calderon et.al unpublished
One copy of p.L144F was detected in a Middle eastern male (with a family history for primary carnitine deficiency) with confirmed diagnosis of cystic fibrosis and presenting with pnemonia, other pulmonary issues, and hepatomegaly. Patient had normal total and free plasma carnitine and high carnitine in urine.
Exon 2 Missense c.430C>T p.L144F Benign Calderon et.al unpublished
Detected in a control sample with no information on transport activity in fibroblasts.
Exon 2 Missense c.430C>T p.L144F Benign Calderon et.al unpublished
Female infant was heterozygous for this variant.
Exon 2 Insertion c.440_442dup p.Ser147dup Unknown Carducci (unpublished)
Italian patient had abnormal NBS and was heterozygous for this mutation.
Exon 2 Missense c.451G>A p.V151M 6 Likely Pathogenic Calderon et.al unpublished
Caucasian patient with abnormal NBS, low free and total plasma carnitine levels, and low transport activity in fibroblasts (suggestive of PCD). This patient was heterozygous for this mutation and p.P46S.
Exon 2 Silent c.453G>A p.V151V 6 Benign Calderon et.al unpublished
Detected in two patient samples but not in controls. cDNA studies of p.V151V does not suggest any impact on mRNA levels. One of the patient samples also had p.T440M and transport activity <6% of normal control.
Exon 2 Silent c.453G>A p.V151V Benign Lemes et. Al unpublished
Latin female patient identified with abnormal NBS. Patient was heterozygous for this silent variation and a stop codon abnormality. Clinical presentations included very low CO and high urine carnitine excretion. Patient must take 150 mg/k/d of L-carnitine to reach acceptable blood CO level. Patient is currently about 16 months and is doing well. (submitted by Dr. Aida Lemes, Sistema Nacional de Pesquisa Neonatal, Montevideo, Uruguai).
Exon 2 Silent c.453G>A p.V151V Benign Calderon et.al unpublished
Caucasian female identified with abnormal NBS was heterozygous for P.P46S and the silent variant p.V151V. Patient had low plasma free and total carnitine.
Exon 2 Deletion c.458_459delTG p.V153AfsX41 <5 Pathogenic Dobrowolski (2005)
Australian patient of Anglo-Celtic ancestry was heterozygous for this mutation (documented as 457_458delTG) and p.R289X.
Exon 2 Deletion c.458_459delTG p.V153AfsX41 Pathogenic Calderon et.al unpublished
Caucasian male child identified with abnormal NBS was heterozygous for this mutation. Patient had low free and total plasma carnitine and high urine excretion.
IVS 2 Splice Site? c.497+4A>C Suspected Benign Calderon et.al unpublished
Male infant identified with abnormal NBS was heterozygous for c.497+4A>C and c.952-25T>C, and had low plasma total and free carnitine.
Exon 3-8 Large Deletion Pathogenic Calderon et.al unpublished
Caucasian adult male on carnitine supplementation, had low total and free plasma carnitine. MLPA analysis identified a large deletion affecting exons 3-8. Patient was homozygous for polymorphism c.652+6A>G and c.824+13C>T (no other mutations were found by sequencing).
Exon 3 Missense c.505C>T p.R169W <5 <1 Pathogenic Wang (2000)
Patient of italian descent was homozygous for this mutation. Another patient was heterozygous for this mutation and W351R. Caucasian female presenting with developmental delay and low total and free plasma carnitine was heterozygous for p.R169W. (Daughter had an abnormal NBS but no mutations were found via full gene sequencing.)
Exon 3 Missense c.506G>A p.R169Q <5 Likely Pathogenic Burwinkel (1999)
This mutation was found together with R282X in a patient of German descent presenting with 'severe dilated cardiomyophathy' at age 2. Patient responded to carnitine supplementation and 'dilated cardiomyopathy' was resolved.
Exon 3 Missense c.523G>A p.V175M Likely Benign Toh DS et al. 2011
Caucasian male infant with abnormal NBS was heterozygous for p. P46S, p.V175M, and p.S231F. Patient presented with low plasma carnitine and low urine output of carnitine.
Exon 3 Missense c.529A>G p.M177V VUS Li (2010)
2-month old male identified with abnormal NBS was heterozygous for p.M177V and p.N32S.
Exon 3 Missense c.529A>G p.M177V VUS Calderon et.al unpublished
Female infant with abnormal NBS was heterozygous for p.M177V and c.1053-3C>T. Patient presented with low plasma carnitine.
Exon 3 Missense c.535A>T p.M179L 92 Benign Koizumi (1999)
Found in one individual of Japanese descent (carrier). Serum free carnitine levels were <5% normal, however, in vitro expression of variant in CHO and HEK cells did not show significant impairment of transport activity.
Exon 3 Missense c.557T>C p.L186P VUS Calderon et.al unpublished
African-American/Caucasian patient with abnormal NBS was heterozygous for p.L186P, p.P398L, and p.P549S and had low total/free plasma carnitine. Other benign variants identified were p.L95L (c.285C>T), c.393+17G>A c.1268-34A>G, c.1587-38A>C.
Exon 3 Missense c.557T>C p.L186P VUS Li (2010)
6-week old female identified with abnormal NBS and presenting with low total and free plasma carnitine was heterozygous for p.L186P. This variant is predicted to be pathogenic by PolyPhen and SIFT (computer based algorithm).
Exon 3 Frame-shift nonsense c.573delG p.N192IfsX12 pathogenic Li (2010)
14-year old male presenting with cardiomyopathy was heterozygous for p.W117X and p.N192IfsX12.
Exon 3 Missense c.605T>C p.L202P VUS Calderon et.al unpublished
Adult female identified with child having abnormal NBS was heterozygous for p.L202P and p.S286P. Child had low free and carnitine.
Exon 3 Missense c.629A>G p.N210S Pathogenic Calderon et.al unpublished
Asian/Oriental patient with abnormal NBS was heterozygous for this mutation and p.A214V. Patient had low total/free plasma carnitine levels.
Exon 3 Missense c.629A>G p.N210S 24 Pathogenic Calderon et.al unpublished
Caucasian male with abnormal NBS ws heterozygous for this mutation. Patient had low free and total plasma carnitine and normal urine carnitine output.
Exon 3 Missense c.632A>G p.Y211C <10 Likely Pathogenic Vaz (1999)
Two unrelated patients were found to be homozygous for this mutation. Patients were from Morocco and Cape Verde respectively.
Exon 3 Missense c.632A>G p.Y211C Likely Pathogenic Calderon et.al unpublished
Hispanic male identified with abnormal NBS was heterozygous for this mutation and homozygous for common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G). Patient has low plasma carnitine, high carnitine excretion in urine and low carnitine transport activity in fibroblasts.
Exon 3 Missense c.641C>T p.A214V Suspected Pathogenic Calderon et.al unpublished
Detected in two patient samples. One sample was also heterozygous for p.R83L. Second sample was heterozygous for p.A214V, p.V448L, and p.H79fsX50 (p.A214V & p.V448L thought to be in cis). Transport activity in second patient's fibroblasts was <1. A third patient of Asian/Oriental descent was heterozygous for this mutation and p.N210S (patient had low total/free plasma carnitine levels). Fourth patient of Asian/Oriental descent was homozygous for p.A214V; identified with abnormal NBS and low total and free plasma carnitine (carnitine levels were normal at age 3 months).
Exon 3 Missense c.641C>T p.A214V Suspected Pathogenic Calderon et.al unpublished
Male child with abnormal NBS was homozygous for A214V and homozygous for common polymorphisms (c.652+6A>G and c.824+13C>T). Patient presented with low free and total plasma carnitine.
Exon 3 Missense c.646G>C p.V216L Uncertain Calderon et.al unpublished
Adult female identified with child having abnormal NBS was homozygous for this variation and two polymorphisms (c.652+6A>G, c. 824+13C>T). Patient had low plasma free and total carnitine and low urine free and total carnitine output.
Exon 3 Missense c.646G>C p.V216L Uncertain Calderon et.al unpublished
Male patient was heterozygous for this variant and homozygous for polymorphisms c.652+6A>G and c.824+13C>T). No other information available.
Exon 3 Insertion c.652_653ins
TATGGCCATCAGGTTGGAG
p.G218VfsX68 2 Pathogenic Lamhonwah & Tein (1998)
Patient of Italian descent was heterozygous for this mutation and p.G12_L477del (large deletion).
Intron 3 Splice Site c.652+1G>A 2 Pathogenic Lamhonwah (2002)
Patient of East India/Irish descent was heterozygous for this mutation and p.F23del. Hwu et al. (2007, JIMD 30 (5): 816) reported a chinese patient (Taiwan) heterozygous for this mutation and p.R254X; this patient was diagnosed with both primary carnitine and N-acetylglutamate synthase deficiency.
Intron 3 c.652+6A>G Polymorphism Calderon et.al unpublished
Patient was homozygous for this variant and the polymorphisms p.L95L (c.285C>T), c.652+77A>G, p.L269L (c.807G>A), c.824+13T>C and heterozygous for c.393+17G>A.
Intron 3 c.652+77A>G Uncertain Calderon et.al unpublished
This variant was found in a Caucasian female indentified with abnormal NBS. This patient was heterozygous for this variant, c.1674+47C>T and p.D122Y. Clinical presentations inclueded hypotonia and low free and total plasma carnitine levels.
Intron 3 Splice Site c.653-2A>C 8 Pathogenic Calderon et.al unpublished
This mutation was detected with p.R399W in patient of unknown ethnicity.
Exon 4 Deletion c.653_824del p.T219SfsX20 2 Pathogenic Lamhonwah & Tein (1998)
Patient of Mexican descent was heterozygous for this mutation and p.G12_L477del.
Exon 4 Missense c.674C>T p.S225L VUS Calderon et.al unpublished
Caucasian/Hispanic was heterozygous for p.S225L. This patient was first identified with abnormal NBS, and later presented with low free/total plasma carnitine, gross motor and speech delay.
Exon 4 Missense c.679G>A p.R227C Uncertain Calderon et.al unpublished
Asian female infant identiied with abnormal NBS was heterozygous for p.R83L and p.R227C. Patient had low plasma carnitine.
Exon 4 Missense c.680G>A p.R227H Pathogenic Li (2010)
Li et al 2011 classified this mutation as deleterious based on predictions using SIFT and Polyphen. In this study this mutation was described in two infants identified with abnormal NBS. The female infant was heterozygous for this mutation (inherited from asymptomatic mother) and a whole gene deletion (thought to be de novo or due to gonadal masaicism since it was not detected in the father). The male was heterozygous for p.R227H and p.T232M. In our laboratory a hispanic male identified with abnormal NBS was found to be heterozygous for p.R488C and p.R227H (patient exhibited low plasma total and free carnitine, and high urine carnitine).
Exon 4 Missense c.680G>A p.R227H Pathogenic Li (2010)
Asymptomatic adult mother was heterozygous for this variant. Child (1-month old female), was identified with abnormal NBS and had one copy of p.R227H inherited from mom and a large deletion (~1.6MB, encompassing the entire OCTN2 gene as well as other genes surrounding it) not found in dad's DNA. Deletion was detected through CGH array.
Exon 4 Missense c.680G>A p.R227H Pathogenic Li (2010)
5-month old male was heterozygous for p.R227H and p.T232M. p.R227H is predicted to be pathogenic by PolyPhen and SIFT (computer bases algorithms).
Exon 4 Missense c.680G>A p.R227H Pathogenic Calderon et.al unpublished
Hispanic male with abnormal NBS was homozygous for p.R227H. Patient had low plasma free and total carnitine, and is now on carnitine supplementation.
Exon 4 Missense c.680G>A p.R227H Pathogenic Calderon et.al unpublished
Female patient with abnormal NBS was heterozygous for p.R227H (inherited from mom). Patient and mother had low plasma carnitine levels.
Exon 4 Missense c.680G>A p.R227H Pathogenic Calderon et.al unpublished
Hispanic female with abnormal NBS was homozygous for p.R227H and polymorphisms c.652+6A>G and c.824+13C>T. Patient had low free and total plasma carnitine and normal carnitine urine excretion.
Exon 4 Missense c.688T>C p.F230L VUS Li (2010)
5-week old female identified with abnormal NBS and having low total and free plasma carnitiene levels was heterozygous for p.F230L and p.P46S.
Exon 4 Missense c.692C>T p.S231F VUS Calderon et.al unpublished
Caucasian female with abnormal NBS and low total and free carnitine in plasma was heterozygous for p.S231F.
Exon 4 Missense c.692C>T p.S231F VUS Calderon et.al unpublished
Caucasian male infant with abnormal NBS was heterozygous for p. P46S, p.V175M, and p.S231F. Patient presented with low plasma carnitine and low urine output of carnitine.
Exon 4 Missense c.695C>T p.T232M 5 2 Pathogenic Calderon et.al unpublished
Anglo-Celtic patient was heterozygous for this mutation and p.T468R.
Exon 4 Missense c.695C>T p.T232M Calderon et.al unpublished
Caucasian female of Italian origin identified via newborn screening, was compound heterozygote: c.[-149G>A];[148delT] (confirmed in parents). Patient is asymptomatic at 8 months.
Exon 4 Missense c.695C>T p.T232M Calderon et.al unpublished
Caucasian female was heterozygous for P.T232M and p.P46S and carnitine transport activity of <6. Patient had low plasma free and total carnitine levels.
Exon 4 Missense c.695C>T p.T232M Calderon et.al unpublished
Caucasian female infant identified with abnormal NBS, presented with mild hypotonia, low free and total plasma carnitine, and was heterozygous for p.T232M.
Exon 4 Missense c.695C>T p.T232M Calderon et.al unpublished
Caucasian male with abnormal NBS was heterozygous for p.T232M and p.Y358N. Patient had low total plasma carnitine.
Exon 4 Missense c.695C>T p.T232M Calderon et.al unpublished
Female infant identified with abnormal NBS was heterozygous for p.T232M. Patient had low plasma carnitine and normal urine excretion.
Exon 4 Missense c.695C>T p.T232M Calderon et.al unpublished
Caucasian female child identified with abnormal NBS was heterozygous for p.T232M. Patient had low free and total plasma carnitine.
Exon 4 Missense c.718G>A p.A240T VUS Li (2010)
35 yr. old female, with intolerance to fasting and low total and free plasma carnitine levels, was heterozygous for p.A240T.
Exon 4 Missense c.725G>T p.G242V <5 <1 Pathogenic Wang (2000)
Patient of Spanish descent was homozygous for this mutation.
Exon 4 Nonsense c.760C>T p.R254X <1 Pathogenic Tang (2002)
Described as a founder mutation in the Chinese where two patients (one from Taiwan, the other Macau) were homozygous for this mutation, and a third patient (Taiwan) was heterozygous for this mutation and p.Y387X. Lamhonwah et al. (2004, J. Inherit. Metab. dis. 27 (4): 473-476) reported a patient from Saudi Arabia homozygous for this mutation. Hwu et al. (2007) reported a chinese patient (Taiwan) heterozygous for this mutation and p.652+1G>A (IVS3).
Exon 4 Missense c.761G>A p.R254Q VUS Calderon et.al unpublished
Caucasian asymptomatic male with abnormal NBS was heterozygous for this mutation and p.R399W. Patient had low free and total plasma carnitine levels.
Exon 4 Missense c.761G>A p.R254Q VUS Calderon et.al unpublished
Asymptomatic female with abnormal NBS was heterozygous for p.R254Q and P46S. Patient had low free and total plasma carnitine, normal urine free carnitine, and low urine total carnitine.
Exon 4 Missense c.761G>A p.R254Q VUS Calderon et.al unpublished
Asymptomatic male with abnormal NBS and low free and total plasma carnitine was heterozygous for p.R254Q and p.R399W.
Exon 4 Missense c.761G>A p.R254Q VUS Calderon et.al unpublished
26 yr. old female with low free carnitine (8; ref=22-55). Patient's child had abnormal NBS and low CO. Symptoms: no history of syncopy, muscle aches or weakness, and occasional rapid heart rates.
Exon 4 Missense c.761G>A p.R254Q VUS Calderon et.al unpublished
2-month old Caucasian male with abnormal NBS was heterozygous for p.R254Q and c.1053-2A>C. Patient shows no symptoms of primary carnitine deficiency and no family history. Plasma carnitine was low, urine carnitine was normal, and urine resorption was reduced (83%).
Exon 4 Missense c.761G>A p.R254Q VUS Calderon et.al unpublished
Caucasian adult female identified with child having abnormal NBS was heterozygous for p.P46S and p.R254Q. Clinical presentations included low plasma free and total carnitine and normal free, low total carnitine excretion in urine.
Exon 4 Missense c.761G>A p.R254Q VUS Calderon et.al unpublished
Adult female identified with child having abnormal NBS was heterozygous for p.R254Q. Patent presented with occasional rapid heart rates, and low plasma free carnitine.
Exon 4 Missense c.761G>A p.R254Q VUS
Caucasian male identified with abnormal NBS was heterozygous for p.R254Q (inherited from mom) and c.1053-2A>C (from dad). Patient was homozygous for common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G) and had low plasma carnitine and normal urine carnitine excretion.
Exon 4 Nonsense c.768G>A p.W256X 0 Pathogenic Amat di San Filippo (2006)
Caucasian patient heterozygous for this mutation and p.T468R.
Exon 4 Missense c.769C>T p.R257W <50 0 Pathogenic Li (2011)
Two caucasian sisters were heterozygous for this missense variant and had low free and total plasma carnitine. Sister and mother presented with mild disease. Patient transport activity in fibroblasts was 49% of normal fibroblasts, mother was 48%. Enzyme activity is null when this mutation is expressed in CHO cells.
Exon 4 Missense c.769C>T p.R257W VUS Li (2010)
30 year-old asymptomatic female was heterozygous for p.R257W and p. T440M. P.R257W is predicted to be pathogenic by PolyPhen and SIFT (computer algorithms).
Exon 5 Missense c.769C>T p.R257W VUS Calderon et.al unpublished
Caucasian hispanic male with abnormal NBS was heterozygous for p.Y211H and p.R257W (and homozygous for polymorphisms c.285T>C, c.652+6A>G, c.807A>G). Patient had low plasma total and free carnitine.
Exon 1 Missense c.769C>T p.R257W Pathogenic Calderon et.al unpublished
Caucasian female with abnormal NBS was heterozygous for p.R257W and p.P398L. Patient had low total(16) and free (10) plasma carnitine.
Exon 4 Missense c.791C>G p.T264R VUS Li (2010)
6-month old male with abnormal NBS and very low total and free plasma carnitine levels was homozygous for p.T264R. This variant is predicted to be pathogenic by PolyPhen and SIFT (computer algorithms).
Exon 4 Deletion c.806delT p.L269HfsX27 2 Pathogenic Cederbaum (2002)
Patient of Mexican descent was homozygous for this mutation (parents were heterozygous). Brother died at age 3 months (not genotyped). RNA analysis revealed three species of cDNA: predicted 295 bp species containing the deletion and leading to p.L269HfsX27 (11% of transcripts), two other species of cDNA containing a 13/19 bp nucleotide insertion between exons 3 and 4 in cis with deletion (89% of transcripts).
Exon 4 Silent c.807G>A p.L269L Benign Tang (2002)  
Intron 4 c.824+13C>T Polymorphism Tang (2002)
Common polymorphism (1 or 2 copies).
Intron 4 c.824+38G>T Suspected Benign Calderon et.al unpublished
Newborn male with abnormal NBS was homozygous for p.F17L and a suspected benign variant in Exon 4 (c.824+38G>T). Patient was homozygous for common polymorphisms (c.285T>C, c.652+6 A>G, and c.807A>G) and had low plasma carnitine.
Exon 5 Nonsense c.825G>A p.W275X 5 Pathogenic Dobrowolski (2005)
Vietnamese patient was heterozygous for this mutation and c.1267+3_23del in exon 7.
Exon 5 Missense c.839C>T p.S280F <1 <1 Pathogenic Amat di San Filippo (2006)
Caucasian patient was heterozygous for this mutation and p.P398L.
Exon 5 Missense c.839C>T p.S280F Pathogenic
Male patient with abnormal NBS and low free and total plasma carnitine was heterozygous for p.A142S, R488H, S280F and homozygous for benign variants c.285T>C, c.652+6A>G, c.807A>G, c.824+13C>T. Mother also had low free and total plasma carnitine.
Exon 5 Deletion c.839delC p.R282NfsX14 1 Pathogenic Lamhonwah (2002)
This mutation was detected in a patient from Croatia. Patient was homozygous for this mutation. Mutation is thought to destroy two transmembrane domains and most likely cause protein to be retained in the cytoplasm.
Exon 5 Missense c.841C>T p.P281S Uncertain Calderon et.al unpublished
Caucasian female child presenting with low free and total plasma carnitine, and hypoglycemia (which improved upon carnitine supplementation). Patient was heterozygous for p.P281S.
Exon 5 Nonsense c.844C>T p.R282X <1 Pathogenic Wang (1999)
Burwinkel et al. 1999 (Biochemical and Biophysical REsearch Communications 261: 484-487) also describes this mutation in two patients of German descent (patient 1 was homozygous for this mutation and transport activity was 10% of normal; patient 2 was heterozygous for this mutation and R169Q and transport activity was 5% of normal. Vaz et al. 1999 (Hum. Genet 105: 157-161) also describes a patient of German descent homozygous for this mutation and nearly no transport activity.
Exon 5 Nonsense c.844C>T p.R282X Pathogenic Calderon et.al unpublished
Caucasian male infant identified with abnormal NBS was heterozygous for this mutation. Patient presented with low plasma carnitine and high urine output of carnitine.
Exon 5 Missense c.845G>A p.R282Q <10 11 Pathogenic Amat di San Filippo (2006)
Hispanic patient was homozygous for this mutation.
Exon 5 Missense c.847T>C p.W283R <1 Pathogenic Mayatepek (2000)
Caucasian patient was heterozygous for this mutation and p.V446F.
Exon 5 Missense c.847T>A p.W283R <10 <5 Pathogenic Amat di San Filippo (2006)
Saudi patient was homozygous for this mutation (parents are related). Patient has 3 unaffected siblings and a brother who died at age 2.
Exon 5 Missense c.849G>T p.W283C 2 Pathogenic Koizumi (1999)
Japanese individual was homozygous for this mutation.
Exon 5 Missense c.856T>C p.S286P VUS Calderon et.al unpublished
Adult female identified with child having abnormal NBS was heterozygous for p.L202P and p.S286P.
Exon 5 Nonsense c.865C>T p.R289X <5 Pathogenic
Hispanic female infant identified with abnormal NBS had low total and free plasma carnitine was heterozygous for p.G152D and p.R289X.
Exon 5 Nonsense c.865C>T p.R289X <5 Pathogenic Dobrowolski (2005)
Australian patient of Anglo-Celtic ancestry was heterozygous for this mutation and p.V153AfsX41.
Exon 5 Missense c.902C>A p.A301D <5 4 Pathogenic Wang (2000)
Patient of italian descent was homozygous for this mutation. Parents were related (first cousins) and siblings died at 10 months of age with SCD like clinical presentations.
Exon 5 Missense c.904A>G p.K302E VUS Calderon et.al unpublished
Burmese female identified with abnormal NBS was heterozygous for p.[L95V;D115G] and p.K302E predicted to be on opposite chromosomes. Patient had low plasma free and total carnitine and was homozygous for common benign variants (c.285T>C, c.652+6A>G, c.807A>G, c.824+13C>T).
Exon 5 Missense c.934A>G p.I312V Benign Li (2010)
Published study describes a four month old male heterozygous with this variant (VUS). Adult female presenting with cardiomyopathy was heterozygous for this variant.
Exon 5 Missense c.934A>G p.I312V VUS Li (2010)
4-month old male presenting with cardiomyopathy was heterozygous for p.I312V.
Exon 6 Nonsense c.955C>T p.Q319X pathogenic Li (2010)
27-year old asymptomatic female presenting with low total and free plasma carnitine levels was heterozygous for this nonsense mutation.
Exon 6 Deletion c.1009delA p.T337RfsX12 16-20 Pathogenic Lamhonwah (2002)
Three patients of Turkish descent were heterozygous for this deletion (documented as T337fsX328) and p.T440M.
Exon 6 Missense c.1043T>C p.I348T Pathogenic Calderon et.al unpublished
Caucasian/African-American female was heterozygous for p.I348T. This patient had high carnitine detected in urine and low plasma carnitine (free and total) and was identified with abnormal NBS.
Exon 6 Missense c.1051T>C p.W351R <5 <1 Pathogenic Wang (2000)
Patient was compound heterozygote for this mutation and R169W.
Intron 6 c.952-25T>C Benign Calderon et.al unpublished
Male infant identified with abnormal NBS, was heterozygous for c.497+4A>C and c.952-25T>C, and had low plasma total and free carnitine.
Intron 6 Splice Site c.1053-3C>T Likely Pathogenic Calderon et.al unpublished
Female infant with abnormal NBS was heterozygous for p.M177V and c.1053-3C>T. Patient presented with low plasma carnitine.
Intron 6 Splice Site c.1053-2A>C Pathogenic Calderon et.al unpublished
2-month old Caucasian male with abnormal NBS was heterozygous for p.R254Q and c.1053-2A>C. Patient shows no symptoms of primary carnitine deficiency and no family history. Plasma carnitine was low, urine carnitine was normal, and urine resorption was reduced (83%).
Intron 6 Splice Site c.1053-2A>C Pathogenic Calderon et.al unpublished
Caucasian male identified with abnormal NBS was heterozygous for p.R254Q (inherited from mom) and c.1053-2A>C (from dad). Patient was homozygous for common polymorphisms (c.285T>C, c.652+6A>G, c.807A>G) and had low plasma carnitine and normal urine carnitine excretion.
Exon 7 Missense c.1064C>T p.S355L VUS Li (2010)
30-yr old asymptomatic female presenting with low total and free plasma carnitine levels was heterozygous for p.Y358N and p.F17L. P.Y358N is predicted to be pathogenic by PolyPhen and SIFT (computer algorithms).
Exon 7 Missense c.1072T>A p.Y358N VUS Li (2010)
6-month old female identified with abnormal NBS was heterozygous for p.Y358N and p.Y449D.
Exon 7 Missense c.1072T>A p.Y358N VUS Calderon et.al unpublished
Caucasian female child presenting with low free and total plasma carnitine was heterozygous for p.Y358N and p.Y449D.
Exon 7 Missense c.1072T>A p.Y358N VUS Calderon et.al unpublished
Caucasian male with abnormal NBS was heterozygous for p.T232M and p.Y358N. Patient had low total plasma carnitine.
Exon 7 Duplication c.1078_1083dupGGGCTT p.G360_L361dup Pathogenic Calderon et.al unpublished
Caucasian female adult identified through child having abnormal NBS presented with fatigue and low free and total plasma carnitine was heterozygous for p.P46S and c.1078_1083dupGGGCTT. Additional caucasian male was seen with abnormal NBS and heterozygous for this variant.
Exon 7 Missense c.1088T>C p.L363P VUS Akpinar (2010)
Patients displayed low carnitine levels in plasma and high carnitine levels in urine.
Exon 7 Nonsense c.1161T>G p.Y387X Pathogenic Tang (2002)
Chinese patient (Taiwan) was heterozygous for this mutation and p.Y254X.
Exon 7 Deletion c.1181_1183delTGC p.L394del 7 Pathogenic Calderon et.al unpublished
Detected in a sample at our lab with p.P46L (both heterozygous).
Exon 7 Missense c.1193C>T p.P398L <1 <1 Pathogenic Amat di San Filippo (2006)
Caucasian patient was heterozygous for this mutation and p.S280F. Additional patient had this mutation with p.P46S. Caucasian female had one copy each of p.A142S, p.R488H and p.P398L. She presented with chronic fatigue and irregular heart beat on occasion. Child had abnormal NBS.
Exon 8 Missense c.1193C>T p.P398L Pathogenic Calderon et.al unpublished
Adult Caucasian female ws heterozygous for p.P398L and presented with hypoglycemia. Patient was identified with child having abnormal NBS and had low plasma free and total carnitine.
Exon 8 Missense c.1193C>T p.P398L Pathogenic Calderon et.al unpublished
Caucasian female with abnormal NBS was heterozygous for p.R257W and p.P398L. Patient had lw total(16) and free (10) plasma carnitine.
Exon 8 Missense c.1193C>T p.P398L Pathogenic Calderon et.al unpublished
Caucasian male infant was homozygous for this mutation. Patient presented with low free and total plasma carnitine. Patient was homozygous for common polymorphisms c.652+6A>G and c.824+13C>T.
Exon 8 Missense c.1193C>T p.P398L Pathogenic Calderon et.al unpublished
Caucasian/African American male was heterozygous for this mutation. Patient presented with normal plasma carnitine. Patient was homozygous for common polymorphisms c.652+6A>G.
Exon 7 Missense c.1195C>T p.R399W VUS El-Hattab (2010)
African American female infant identified with abnormal NBS and low total, free, and acyl-carnitine plasma carnitine was heterozygous for p.R399W. Mother was heterozygous for p. R399W and p.A442I and had low total, free, and acyl-carnitine in plasma. Brother was heterozygous for p.R399W and half-sister was heterozygous for p.A442I (both had low plasma carnitine). This mutation is predicted to be deleterious by SIFT and PolyPhen computer algorithms.
Exon 7 Missense c.1195C>T p.R399W 36 7 Pathogenic Calderon et.al unpublished
Detected in a carrier sample with p.G12S and a patient sample with no other mutations (heterozygous). Transport activity in fibroblasts was 36 for the carrier and <10 for patient. This mutation was detected with p.R282X in a patient identified with abnormal newborn screening and very low total and free plasma carnitine . Patient is currently on carnitine supplementation.
Exon 7 Missense c.1195C>T p.R399W Calderon et.al unpublished
Asymptomatic male with abnormal NBS and low free and total plasma carnitine was heterozygous for p.R254Q and p.R399W.
Exon 7 Missense c.1196G>A p.R399Q <1 <5 Pathogenic Wang (2001)
Two Jewish siblings of Iranian descent were homozygous for this mutation. Parents were first cousins.
Exon 7 Insertion c.1202_1203insA p.Y401X <5 Pathogenic Wang (1999)
Patient was caucasian and compound heterozygote for this mutation and p.G434AfsX24 (1 bp deletion in exon 8). Lamhonwah et al. reported a caucasian homozygous for p.Y401X who had <5% transport activity in cultured fibroblasts compared to normal control (2002, Am. J of Med. Gen. 111: 271-284).
Exon 7 Insertion c.1202dupA p.Y401X 18 Pathogenic Calderon et.al unpublished
Caucasian female with child having abnormal NBS was heterozygous for this frame shift causing mutation. Patient presented with low free and total plasma carnitine and low urine output of carnitine. Transport activity was 18% of normal. Patient felt weak and fatigued.
Exon 7 Insertion c.1250het_dupT p.M417IfsX106 Pathogenic Calderon et.al unpublished
Caucasian female infant identified with abnormal NBS, low free and total plasma carnitine (free and acetyl carnitine markedly reduced), and normal urine carnitine levels was heterozygous for c.1250dupT and p.P455R.
Intron 7 Deletion c.1267+3_+24del22 pathogenic Li (2010)
1-year old male identified with abnormal NBS was heterozygous for this deletion and p.F17L.
Intron 7 Deletion c.1267del+3_+23 5 Pathogenic Dobrowolski (2005)
Vietnamese patient was heterozygous for this mutation and p.W275X. This deletion is thought to impact splicing after exon 7, however, RNA studies have not been performed.
Intron 7 c.1268-34A>G Benign Calderon et.al unpublished
c.1268-34A>G was detected in an African-American/Caucasian patient with low total/free plasma carnitine and was heterozygous for p.L186P, p.P398Lp.P549S. Other benign variants detected were p.L95L (c.285C>T), c.393+17G>A, and c.1587-38A>C. A second patient of African-American descent was heterozygous for p.P549S, p.W132X, and p.T232M (and likely benign variants c.393+17G>A, c.1268-34A>G, and c.1587-38A>C).
Exon 8 Deletion c.1302delG p.G434AfsX24 <5 Pathogenic Wang (1999)
Detected in patient with p.Y401X (both heterozygous). Documented as G435fsX458.
Exon 8 Deletion c.1304_1313del10 p.G435EfsX20 pathogenic Li (2010)
30-year old female presenting with easy fatigability was heterozygous for this deletion and p.T232M.
Exon 8 Missense c.1319C>T p.T440M <1 <1 Pathogenic Lamhonwah (2002)
Patient of Croatia origin and homozygous for this mutation. Carnitine uptake in cultured lymphoblasts was 0.5% of normal control. This patient was also diagnosed with 3-methylglutaconic aciduria (Maradin el al 2000, Journal of Inherited Metabolic Disorder 23 (S1): 118; conference abstract). Lamhonwah also reports 3 Turkish and 1 caucasian patient heterozygous for this mutation and another mutation (p.T337RfsX12 in the Turkish patients, and p.R169W in caucasian patient).
Exon 8 Missense c.1327T>G p.F443V VUS Li (2010)
31-year old asymptomatic female was heterozygous for p.F443V. This variant is predicted to be pathogenic by PolyPhen and SIFT (computer algorithms).
Exon 8 Missense c.1336G>T p.V446F <1 Pathogenic Mayatepek (2000)
Caucasian patient was heterozygous for this mutation and p.W283R.
Exon 8 Missense c.1340A>G p.Y447C <15 0 Pathogenic Rahbeeni (2002)
Patient described was from Saudi Arabia and homozygous for this mutation. Amat di San Filippo and Longo (2004, The Journal of Biological Chemistry 279(8):7247-7253) showed that this mutation prevents maturation of the protein into the plasma membrane and abolishes transport activity.
Exon 8 Missense c.1342G>T p.V448L <1 VUS Calderon et.al unpublished
Detected in a patient sample with p.A214V and p.H79fsX50 (p.A214V & p.V448L thought to be in cis).
Exon 8 Missense c.1345T>G p.Y449D 50 11 Pathogenic Amat di San Filippo (2004)
Caucasian female child presenting with low free and total plasma carnitine was heterozygous for p.Y358N and p.Y449D.
Exon 8 Missense c.1345T>G p.Y449D 50 12 Pathogenic Amat di San Filippo (2004)
Patient of unknown ethnicity was heterozygous for this mutation. No other mutations in SLC22A5 were found, however, variations in other genes involved in the fatty acid oxidation pathway were previously descrived (Vockley et al. 2000, Mol. Genet. Metab. 71: 10-18). African American female was homozygous for this mutation, and was placed on carnitine supplementation where symptoms improved. Patient's male child was heterozygous for this mutation but also presented with low levels of plasma and free carnitine and was also given carnitine supplementation.
Exon 8 Missense c.1354G>A p.E452K <5 <5 Pathogenic Wang (2000)
Pakistani patient was homozygous for this mutation.
Exon 8 Missense c.1364C>G p.P455R VUS Calderon et.al unpublished
Caucasian female infant identified with abnormal NBS, low free and total plasma carnitine (free and acetyl carnitine markedly reduced), and normal urine carnitine levels was heterozygous for c.1250dupT and p.P455R.
Exon 8 Missense c.1364C>G p.P455R VUS Li (2010)
6-month old male identified with abnormal NBS was heterozygous for p.P455R. This variant is predicted to be pathogenic by PolyPhen and SIFT (computer algorithms).
Exon 8 Missense c.1364C>G p.P455R VUS Calderon et.al unpublished
Caucasian adult female was heterozygous for p.P46S and p.P455R; and homozygous for polymorphisms (c.285T>C,c.652+6A>G, c.807A>G). Patient had low total.free plasma carnitine and normal carnitine in urine.
Exon 8 Indel c.1392_1409delinsCA p.V465TfsX29 <1 Pathogenic Calderon et.al unpublished
Patient was homozygous for this mutation.
Exon 8 Missense c.1400C>G p.S467C <8 11 (HEK293) Pathogenic Koizumi (1999)
First reported in an individual of Japanese descent (carrier). Schimmenti et al. (2007, Molec. Gen. and Met. 90 (4):441-115) detected this mutation with p.R254X in a mother identified via newborn screening. Female patient had one copy each of this mutation and p.G96A; presented with low plasma carnitine levels (free and total). Child inherited p.S467C from mom and presented with low free and total plasma carnitine.
Exon 8 Missense c.1403C>G p.T468R <6 <1 Pathogenic Lamhonwah (2002)
Patient of unknown ethnicity was heterozygous for this mutation and p.I89GfsX45 (due to an 11 bp duplication in exon 1). Amat di San Filippo et al. (2006, Hum. Mut. 27(6):513-523) described a caucasian patient heterozygous for this mutation and p.W256X with no transport activity.
Exon 8 Missense c.1403C>G p.T468I Likely Pathogenic Calderon et.al unpublished
Middle Eastern female with abnormal NBS was homozygous for p.T468I (and homozygous for polymorphisms c.285T>C, c.652+6A>G, c.807A>G). Patient had low plasma free and total carnitine and high carnitine output. Patient's parents are first cousins.
Exon 8 Missense c.1409C>T p.S470F 7.1 Likely Pathogenic Lamhonwah (2002)
Asian patient was homozygous for this mutation.
Exon 8 Missense c.1411C>T p.R471C VUS Carducci (unpublished)
Italian patient was identified with abnormal NBS and was compound heterozygous with p.G12S.
Exon 8 Missense c.1412G>A p.R471H <10 <2 Pathogenic Spiekerkoetter (2003)
A father and two sons (ages 11 months and 5 yrs.) of Turkish origin were homozygous for this mutation (mother was heterozygous). Carnitine transport activity in fibroblast was deficient in all three cases, however, only the youngest child was symptomatic. Amatt di San Filippo et al. (2006, Human Mutation 27(6):513-523) show significant imparement of transport activity in CHO cells caused by this mutation.
Exon 8 Missense c.1433C>T p.P478L 5 <1 Pathogenic Tang (1999)
Chinese patient was heterozygous for this mutation and p.T132X. Elder sister died in first year of life.
Exon 8 Missense c.1441G>T p.V481F >60 Slight reduction in transport activity Urban (2006)
Expression studies found that transport activity was not significantly impared by this mutation alone. Patient was heterozygous for this variant.
Exon 8 Missense c.1441G>A p.V481I Suspected Benign Calderon et.al unpublished
Caucasian female identified with child having abnormal NBS was heterozygous for this variant. Patient had low plasma (free + total) carnitine and high urine output of carnitine (free + total).
Intron 8 Splice Site c.1451-1G>A <10 Pathogenic Nezu (1999)
Patient was homozygous for this mutation. This variation is thought to disrupt splicing at the end of exon 8, although, RNA studies were not performed.
Exon 9 Missense c.1462C>T p.R488C <4 Pathogenic Schimmenti (2007)
Hispanic male identified with abnormal NBS was found to be heterozygous for p.R488C and p.R227H (patient exhibited low plasma total and free carnitine, and high urine carnitine).
Exon 9 Missense c.1463G>A p.R488H 5 47 Pathogenic Amat di San Filippo (2006)
Caucasian patient was heterozygous for this mutation and p.A142S (inherited from mom), and p.T440M (inherited from dad). Expression of this mutation alone in CHO cells did not significantly impare carnitine transport, however, carnitine transport was significantly reduced when this mutation was expressed in cis with p.A142S. Additional affected female patient with <5 micromoles/L of total free plasma carnitine inherited p.A142S/p.R488H from one parent and c.1586+1 G>T from other parent. Patient was treated for cardiac arrest and possible cardiomyopathy. Heart function improved with carnitine supplementation. This mutation was also detected in two African American brothers, and an unrelated female patient, with p.R488H (expected to be on the same chromosome) and p.P46S. Caucasian female had one copy each of p.A142S, p.R488H and p.P398L.
Exon 9 Missense c.1463G>A p.R488H Pathogenic
Male patient identified with abnormal NBS (low free and total plasma carnitine) was heterozygous for p.A142S, R488H, S280F and homozygous for benign variants c.285T>C, c.652+6A>G, c.807A>G, c.824+13C>T. Mother also had low free and total plasma carnitine.
Exon 9 Missense c.1463G>A p.R488H Pathogenic
Adult female was heterozygous for p.R488H and p.R289X (homozygous for all common polymorphisms as previous case).
Exon 9 Missense c.1463G>A p.R488H Pathogenic
Caucasian adult female was heterozygous for p.A44V and p.[A142S,R488H]; and homozygous for common polymorphisms.
Exon 9 Missense c.1463G>A p.R488H Pathogenic
Caucasian adult male presenting with fatigue and weakness was heterozygous for p.[A142S, R488H].
Exon 9 Missense c.1463G>A p.R488H Pathogenic Calderon et.al unpublished
Female patient with abnormal NBS was heterozygous for p.A142S and p.R488H. Patient was fussy and had GI disconfort, and presented with plasma carnitine levels of 17 (F) and 30 (T).
Exon 9 Missense c.1463G>A p.R488H Pathogenic Calderon et.al unpublished
Caucasian/Native American male with abnormal NBS was heterozygous for p.[A142S; R488H]. Patient had low free/total plasma carnitine.
Exon 9 Missense c.1463G>A p.R488H <21 Pathogenic Calderon et.al unpublished
Caucasian adult female was heterozygous fro p.[A142S; R488H] and presented with fatigue. Patient had low free/total plasma carnitine and fibroblast carnitine transport activity was <21% of normal.
Exon 9 Missense c.1463G>A p.R488H Pathogenic Calderon et.al unpublished
Caucasian infant female identified with abnormal NBS was heterozygous for p.N32S and p.[A142S;R488H]. Patient had low free and total plasma carnitine and normal urine output.
Exon 9 Missense c.1463G>A p.R488H Pathogenic Calderon et.al unpublished
Female Caucasian child was heterozygous for p.[A142S;R488H]. Patient presented with low plasma carnitine.
Exon 9 Missense c.1493T>A p.L498Q VUS Carducci (unpublished)
Italian patient had abnormal NBS and was compound heterozygous for p.G15Gfs*28, Intron 1 c.394-16T>A, and Exon 9 p.L498Q.
Exon 9 Missense c.1520T>C p.L507S VUS Li (2010)
1.5-year old with low total and free plasma carnitine was heterozygous for p.L507S and p.R169W. This variant is predicted to be pathogenic by PolyPhen and SIFT (computer algorithms).
Exon 9 Missense c.1520T>C p.L507S VUS Li (2010)
25-year old male with low total and free plasma carnitine was heterozygous for p.P46S and p.L507S.
Exon 9 Deletion c.1556dupACAC p.I521HX3 <5 Pathogenic Schimmenti (2007)
Identified in a mother via newborn screening. Patient was heterozygous for mutation and p.P46S.
Intron 9 Splice Site c.1586+1G>T Pathogenic Calderon et.al unpublished
Caucasion female patient with <5 micromoles/L of total and free plasma carnitine. Inherited this mutation from mom and p.A142S/p.R488H from dad. Patient was treated for cardiac arrest and possible cardiomyopathy. Heart function improved with carnitine supplementation.
Exon 10 Frameshift c.1596_1597delCA p.H532QfsX21 Pathogenic Calderon et.al unpublished
Caucasian female infant presenting with low free and total plasma carnitine which improved after supplementation was heterozygous for this frameshift mutation.
Exon 10 Missense c.1645C>T p.P549S Benign Dobrowolski (2005)
p.P549S was described in the literature to be clinically insignificant. In our lab this variant was detected in an African-American/Caucasian male who was also heterozygous for p.L186P and p.P398L (and benign variants p.L95L, c.393+17G>A c.1268-34A>G, and c.1587-38A>C, ). Another patient of African-American descent was heterozygous for p.P549S, p.W132X, and p.T232M (and benign variants c.393+17G>A, c.1268-34A>G and c.1587-38A>C).
Exon 10 Missense c.1645C>T p.P549S Benign Calderon et.al unpublished
African-american male presenting with hypoglycemia, cardiomyopathy and history of glycogen storage disease was homozygous for p.P549S and the benign variants c.393+17G>A, c.1268-34A>G, c.1587-38A>C.
Exon 10 Missense c.1645C>T p.P549S VUS Li (2010)
2-year old male presenting with developmental delay, failure to thrive, and myopathy was heterozygous for p.P549S.
Intron 9 c.1587-38A>C Benign Calderon et.al unpublished
This likely benign variant was identified in an African-American/Caucasian patient with abnormal NBS and heterozygous for p.L186P, p.P398L, p.P549S and had low total/free plasma carnitine. Other benign variants identified were p.L95L (c.285C>T), c.393+17G>A, c.1268-34A>G. Another patient of African-American descent was heterozygous for p.P549S, p.W132X, and p.T232M (and variants c.393+17G>A, c.1268-34A>G and c.1587-38A>C).
3'UTR c.1674+47C>T VUS Calderon et.al unpublished
This benign variant was seen in various patient samples as follows: first patient, Caucasian female (identified through via an abnormal NBS of her child) was heterozygous for p.T232M and c.1674+47C>T (mother is currently on carnitine supplementation); second patient was heterozygous for c.1674+47C>T and presented with low free/total plasma carnitine, hypoglycemia, severe ketosis, and acidosis after infection/dehydration event a year prior; third patient was a Caucasian male heterozygous for p.P46S and c.1674+47C>T, presenting with muscle cramps, hyperCKemia, and low free/total plasma carnitine; third patient was a Caucasian female heterozygous for p.D122Y and c.1674+47C>T identified with abnormal NBS, presenting with hypotonia and low total/free plasma carnitine; fourth patient, a Caucasian female heterozygous for c.1674+47C>T and homozygous for common polymorphisms (c.285T>C, c.652+6A>G, c.652+77A>G, c.807A>G, c.824+13C>T) presented with cardiomyopathy and low total/free plasma carnitine; fifth patient, a Caucasian male heterozygous for c.1674+47C>T and p.D138D (c.414C>T) presenting with hypotonia and low free/total plasma carnitine.