SPRED1 Database

  • Reference sequences were NC_000015.9 and NM_152594.2. 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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Click for a detailed description of: NIH Diagnostic Criteria for NF1


164 variants found

Genomic Position Location ▾ Mutation Type Nucleotide Change Protein Change Classification Legius Syndrome Phenotype References Comments
Exon 1-7 Large deletion c.1-845-?_c.32+8517+?del p.0 Pathogenic Legius syndrome Messiaen  
Promoter-Exon 1 Large deletion c.1-?_c.32+? p.0 Pathogenic Multiple CALMs, mild learning disabilities; found in father who had multiple CALMs. Spencer (2011)
Heterozygous deletion of the promoter region and exon 1 [Chr15:g.(36169075_36253662__(36365367_36372927)del (NCBI Build 36.1). Does not meet NF1 criteria. Other findings: posteriorly rotated ears and ptosis of the left eye, xanthelasmas under the eyelid and patchy areas of iris pigmentation in addition to a few large deep iris crypts.
Promoter-Exon 4 Large deletion c.1-1175-?_c.423+19+?del p.? Pathogenic Legius syndrome Brems (2012)
Patient also carries a duplication on 15q26.1 encompassing at least 857kb -18 genes
Exon 1-7 Large deletion c.1-?_c.1335+? p.0 Pathogenic Multiple CALMs, speech delay and mild developmental delay. Spencer (2011)
Heterozygous deletion of the entire SPRED1 gene spanning ~6.6 Mb of chromosome 15 [arr 15q13.3q14(30965692-37586958)x1] (NCBI Build 36.1). Mutation is de novo. Does not meet NF1 criteria. Other findings: isolated cleft palate.
Exon 1-7 Large deletion c.1-?_c.1335+? p.0 Pathogenic Multiple CALMs and axillary freckling. Spencer (2011)
Heterozygous deletion of the entire SPRED1 gene and flanking genes TMCO5A and FAM98B. [Chr15g.(35579596_35632785)_(36511058_36573378)del (NCBI Build 36.1). Does not meet NF1 criteria. No family history of NF1. Other findings: pectus excavatum.
Exon 1 Missense c.2T>C p.Met1? Uncertain Multiple CALMs, axillary and inguinal freckling, cephalalgia, learning disability, ADHD and developmental delay. Pasmant (2009)
Present in all affected family members and absent in non-affected family members. NF1 clinical diagnosis. Mutation tracked with the disease. Other findings: cephalalgia.
Exon 1 Nonsense c.7G>T p.Glu3* Pathogenic Multiple CALMs and hyperactivity. Messiaen (2009)
Patient did not meet NF1 criteria. Other findings: mild hearing loss.
Exon 1 Frameshift c.7_20delGAGGAGACGGCGAC p.Glu3Phefs*2 Pathogenic Multiple CALMs, axillary and inguinal freckling, head circumference in the 10-25th percentile. Messiaen (2009)
Patient met NF1 criteria. Other findings: clindactyly of the 5th finger, mild pulmonic valve stenosis and mitrial valve prolapse.
Exon 1 Frameshift c.18delG p.Thr7Leufs*15 Pathogenic Legius syndrome Pasmant
Normal cognitive development.
Exon 1 Frameshift c.22delT p.Ser8Leufs*14 Pathogenic Legius syndrome Messiaen  
Exon 1 Missense c.26A>T p.Asp9Val Uncertain Brems (2012)
Classified as uncertain by authors (Brems). NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.02%.
Exon 1 Synonymous c.27C>T p.= Benign Multiple CALMs Trevisson  
Exon 1 Missense c.30C>A p.Asn10Lys Suspected Benign Brems (2012)
NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.02%.
Exon 1 Splice Site c.32+2T>C p.? Pathogenic Multiple CALMs Messiaen  
Exon 2-4 Frameshift c.33-17014_423+568delins5 p.Asn12Profs*17 Pathogenic Legius syndrome Messiaen  
Exon 2-4 Deletion c.33-5928-?_c.423+19+?del p.Asn12Profs*17 Pathogenic Legius syndrome Messiaen
r.33_423del
Exon 2-6 Frameshift c.33-20604_c.684+401delinsGAAA p.Asp11Glufs84 Pathogenic Multiple CALMs, bilateral axillary and inguinal freckling, ADHD and lipomas. Spencer (2011)
Identified through RT-PCR and confirmed by MLPA and cloning of the breakpoint. Does not meet NF1 criteria. Variant tracked with disease. Other findings: Patient was referred for possible Noonan syndrome phenotype.
Exon 1 Synonymous c.42T>C p.= Benign Multiple CALMs, other small pigmented spots and axillary freckling. Messiaen (2009)
Patient did not meet NF1 criteria. Other findings: variant was not found in sibling who also had multiple CALMs.
Exon 2 Synonymous c.42T>C p.= Uncertain Messiaen (2009)
r.=
Exon 2 Nonsense c.46C>T p.Arg16* Pathogenic Multiple CALMs and learning disability (Pasmant). Multiple CALMs and punctate freckling in groin (Spurlock). Pasmant (2009)
Met NF1 criteria. Other findings: patient developed monoblastic leukemia and had a clinical diagnosis of NF1 (Pasmant 2009). Also reported in Spurlock 2009, Messiaen 2009 and Spencer 2011.
Exon 2 Nonsense c.52C>T p.Arg18* Pathogenic Multiple CALMs, thoracic freckling, head circumference in the 75-90th percentile, speech delay with normal intelligence, meatal stenosis, hypertelorism, mild hearing loss in left ear (Messiaen). Multiple CALMs, axillary and inguinal freckling, learning di Messiaen (2009)
Patient met NF1 criteria in Muram-Zborovski 2010 and Denayer 2010 but did not meet NF1 criteria in Messiaen 2009. Mutation was de novo and parents had no CALMs; other findings: meatal stenosis, hypertelorism, mild hearing loss in left ear (Messiaen 2009); hypertelorism, congenital hypothyroidism, generalized epilepsy and Parkinson disease with MRI: lesions nucleus caudatus (Denayer 2010); patient had a clinical diagnosis of NF1 and iris crypts that were mistaken for Lisch nodules (Muram-Zborovski 2010). Also reported in Spencer 2011.
Exon 2 Synonymous c.60G>C p.= Benign
rs367745143. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 2 Insertion c.60_61insC p.Val21Argfs*6 Pathogenic Multile CALMs, head circumference in the 50-75th percentile and hyperactivity. Messiaen (2009)
Did not meet NF1 criteria. Other findings: mild pectus excavatum, mild retrognatia and simple ears.
Exon 2 Nonsense c.70C>T p.Arg24* Pathogenic Multiple CALMs, mild to no freckling, head circumference percentile ranged from 3-97, lipomas, developmental delay and ADHD as well as one family member with cataract and another with eczema (Brems). Multiple CALMs, no other NF1 diagnostic signs (Spencer) Brems (2007)
Other findings: cataract and another with eczema in one family member (Brems 2007); low posterior hairline and one family member with Parkinson's disease (Denayer 2010). In Messiaen 2009 the variant was found in 2 families: in each family the variant was also found in a family member who did not fit NIH criteria. Also reported in Spencer 2011.
Exon 2 Missense c.71G>A p.Arg24Gln Uncertain Multiple CALMs, no other NF1 diagnostic signs. Spencer (2011)
Family and functional studies needed to assess pathogenicity.
Exon 2 Duplication c.87_88dupTG p.Gly30Valfs*11 Pathogenic Multiple CALMs, no other NF1 diagnostic signs. Spencer (2011)
Previously reported (Brems 2013)
Exon 2 Missense c.88G>A p.Gly30Arg Uncertain Multiple CALMs, no other NF1 diagnostic signs. Spencer (2011)
Family and functional studies needed to assess pathogenicity.
Exon 2 Missense c.91T>A p.Trp31Arg Uncertain Messiaen  
Exon 2 Missense c.92G>T p.Trp31Leu Uncertain Legius syndrome Messiaen  
Exon 2 Missense c.93G>T p.Trp31Cys Pathogenic Multiple CALMs, axillary freckling, developmental delay and ADHD. Denayer (2010)
Did not meet NF1 criteria. Pathogenic: Trp31Cys mutant was unable to suppress the EGF induced Elk-1 dependent transcription activation; mutation was de novo; other findings: pectus excavatum, hypertelorism, downslanting palpebral fissures, ptosis, low implanted posteriorly rotated ears, low posterior hairline, mild implanted ears, prooptosis, eczema, asthma and strabismus. Classified as pathogenic (Brems 2013)
Exon 2 Frameshift c.107_110delGGAG p.Gly36Valfs*3 Pathogenic Legius syndrome Messiaen  
Exon 2 Frameshift c.108delG p.Ser37Valfs*3 Pathogenic Legius syndrome Messiaen  
Exon 2 Missense c.124G>A p.Val42Ile Uncertain Legius syndrome and found in a patient with NF2 mutation (Spencer 2011). No signs of Legius syndrome; has acute myeloblastic leukaemia (Pasmant). Spencer (2011)
Female, 9.9y/o, had no typical cutaneous symptoms of Legius syndrome, and no NF1 characteristic complications, patient had AML(acute myeloblastic leukaemia), M4 with basophiles excess Leukaemia, BM cell karyotype: 46,XX,t(6;9), (p23;q34)[23]/46,XX [2]. DEK-CAN fusion FLT3-ITD associated molecular lesions. This mutation affects the N-terminus Ena/vasodilator-stumilated phophoprotein homology (Pasmant 2014). NHLBI Exome Sequencing Project minor allele frequency: AA 0.07%, EA 0.02%.
Exon 2 Missense c.131T>A p.Val44Asp Suspected Pathogenic Multiple CALMs, freckling and head circumference ranging from normal to 98th percentile. Spurlock (2009)
Classified as suggested pathogenic (Brems 2013).
Exon 2 Nonsense c.148C>T p.Gln50* Pathogenic Brems (2012)  
Exon 2 Frameshift c.177delT p.Phe59Leufs*62 Pathogenic Mao et al, unpublished
Internal case.
Exon 2 Missense c.184G>C p.Gly62Arg Suspected Pathogenic Multiple CALMs. Mao et al, unpublished
Internal case.
Exon 2 Nonsense c.190C>T p.Arg64* Pathogenic Multiple CALMs (Brems). Mutation tracked with disease, multiple CALMs, macrocephaly, axillary and inguinal freckling, lipoma, learning disability and cephalalgia (Pasmant). Multiple CALMs, bilateral axillary freckling, head circumferences ranged from the Brems (2007)  
Exon 2 Missense c.191G>A p.Arg64Gln Uncertain
rs372205720. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Intron 2 Frameshift c.207+1G>T p.Asp11Glufs*52 Pathogenic Legius syndrome Wimmer
r.33_207deL
Exon 3 Missense c.211G>A p.Val71Ile Uncertain
rs369150309. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 3 Nonsense c.217G>T p.Glu73* Pathogenic Multiple CALMs, head circumference in the 9th and 9oth percentile. Spurlock (2009)
Met NF1 criteria. Other findings: protruding ears.
Exon 3 Missense c.221G>T p.Cys74Phe Benign Multiple CALMs, freckling only in hyperpigmented quadrant, segmental pigmentary NF phenotype. Messiaen (2009)
ProbablyBenign: Elk-reporter assay: WT, PC12-assay: WT, evolutionarily conserved, SIFT: not tolerated, PolyPhen: probably damaging, family studies do not support pathogenicity: variant also present in mother with no clinical signs. Listed as p.Cys74Arg in results section. Classified asBenign (Brems 2013).
Exon 3 Nonsense c.229A>T p.Lys77* Pathogenic Legius syndrome Messiaen  
Exon 3 Missense c.239T>G p.Leu80Arg Uncertain Multiple CALMs. Spencer (2011)
Family and functional studies needed to assess pathogenicity. Characterized as unclassified (Brems 2013).
Exon 3 Frameshift c.242_256delTTTATAATAAGGTCA p.Ile81_Val85del Pathogenic Multiple CALMs (Brems). Multiple CALMs, some axillary and inguinal pigmentation, head circumference in the 60th percentile, normal brain MRI and pectus excavatum (Messiaen 2009). Brems (2007)
Met NF1 criteria. Other findings: normal brain MRI and pectus excavatum (Messiaen 2009).
Exon 3 Missense c.263C>A p.Thr88Lys Uncertain Legius syndrome Pasmant  
Exon 3 Frameshift c.269delA p.His90Profs*31 Pathogenic Brems (2012)  
Exon 3 Missense c.270C>G p.His90Gln Uncertain NF1 Messiaen
Patient and affected parent also carry NF1 mutation.
Exon 3 Frameshift c.271delC p.His91Thrfs*30 Pathogenic Multiple CALMs. Messiaen (2009)  
Exon 3 Missense c.274T>C p.Trp92Arg Uncertain Legius syndrome Messiaen  
Exon 3 Frameshift c.283delG p.Asp95Metfs*26 Pathogenic Legius syndrome Messiaen  
Exon 3 Synonymous c.291G>A p.= Benign Muram-Zborovski (2010)
High frequency in population. rs7182445. NHLBI Exome Sequencing Project minor allele frequency: AA 31.32%, EA 10.30%. This variant was never found as an isolated event but as a haplotype involving c.1044C>T, c.424-8A>C or c.424-98C>T (Muram-Zborovski 2010).
Exon 3 Missense c.299G>A p.Gly100Asp Uncertain Not given. Brems (2012)
Characterized as unclassified (Brems 2013).
Exon 3 Frameshift c.303dupT p.Thr102Asnfs*7 Pathogenic Legius syndrome Denayer (2010)  
Exon 3 Frameshift c.304dupA p.Thr102Asnfs*7 Pathogenic Multiple CALMs (Brems). Multiple CALMs and learning difficulties (Denayer). Brems (2007)
Met NF1 criteria. Somatic mutation from a CALM (Brems 2007). Also found as a germline mutation with one family member with out CALMs; other findings: desmoid rumor abdominal wall (Denayer 2010). Pathogenic: loss of function mutation (Spencer 2011).
Exon 3 Frameshift c.305delC p.Thr102Serfs*19 Pathogenic Multiple CALMs. Spencer (2011)  
Exon 3 Missense c.305C>G p.Thr102Arg Pathogenic Multiple CALMs, some axilary and inguinal freckling, head circumferences ranging from the 25-75th percentile. Messiaen (2009)
Met NF1 criteria. Loss of function missense mutation: Elk-reporter assay: defect, PC12-assay: defect, evolutionarily conserved, SIFT: not tolerated, PolyPhen: probably damaging, supported by family studies. Other findings: large right temporal venous anomaly in brain, progressive dystonia of unexplained etiology in one family member and a vascular anomaly in the left lower leg of another (Messiaen 2009). Unable to bind neurofibromin and recruit neurofibromin to the cell membrance (Brems 2013).
Exon 3 Missense c.305C>A p.Thr102Lys Suspected pathogenic Legius syndrome. Spencer (2011)
Family and functional studies needed to assess pathogenicity.
Exon 3 Missense c.305C>T p.Thr102Met Suspected pathogenic Legius syndrome. Spencer (2011)
Family and functional studies needed to assess pathogenicity.
Exon 3 Frameshift c.320_333delCTGATGCTAGGGCT p.Ala107Valfs*2 Pathogenic Multiple CALMs, axillary/inguinal freckling and head circumferences ranging from 50th to greater than the 97th percentile. Messiaen (2009)
Met NF1 criteria.
Exon 3 Frameshift c.326_329dupCTAG p.Ala110Serfs*2 Pathogenic Multiple CALMs (Messiaen). Multiple CALMs, axillary freckling, ADHD (Denayer 2010). Messiaen (2009)
Other findings: pectus excavatum, implanted ears, prooptosis, MRI: bilateral temporal subcortical white matter lesions (Denayer 2010). Also reported in Spencer 2011.
Exon 3 Frameshift c.331dupG p.Ala111fs Pathogenic Legius syndrome Pasmant 2014
greater than 5 CALMs and lentigines.
Exon 3 Frameshift c.340dupA p.Arg114Lysfs*20 Pathogenic Multiple CALMs, learning dificulties Denayer (2010)
Epicanthal folds, ptosis, pactus carinatum.
Exon 3 Missense c.347T>A p.Ile116Asn Uncertain Legius syndrome Messiaen
Mutation tracks with the disease
Exon 3 Nonsense c.349C>T p.Arg117* Pathogenic Multiple CALMs, lipomas, and head circumference percentile ranging from 25-97. Multiple CALMs and developmental delay (Denayer). Brems (2007)
Other findings: depigmented spots, Noonan-like facial features, mild pectus excavatum, loose integument (2 separate families), Pseudotumor orbitae, tuberous hemangioma, naevus flammeus, hemihyperplasia, accessory nipple, appendicular skin tumor, VUJ-stenosis and nephrolithiasis were found in different people only once; found in two families (Brems 2007); mild synophris, down-slanting palpebral fissures, high arched palate, protruding ears, telecanthus, low implanted ears with thick helix, hypertelorism, short neck, mild webbing, developmental delay (Denayer 2010). Also reported in Messiaen 2009 and Spencer 2011.
Exon 3 Missense c.353G>A p.Arg118Lys Uncertain
rs373381933. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 3 Frameshift c.360dupA p.Glu121Argfs*13 Pathogenic Multiple CALMs and learning disability. Denayer (2010)
Patient did not meet NF1 criteria. Other findings: epicanthal folds, ptosis, pectus carinatum, patient also had Marfan syndrome: positive for FBN1 mutation, prolapse of mitral and tricuspid valve and wide aortic root.
Exon 3 Frameshift c.361delG p.Gly121Argfs*13 Pathogenic Legius syndrome Messiaen  
Exon 3 Frameshift c.375delA p.Gln125fs Pathogenic Legius syndrome Pasmant (2014)  
Intron 3 Intronic c.377-10A>G p.? Benign
rs376134678. NHLBI Exome Sequencing Project minor allele frequency: AA 0.05%, EA 0.00%.
Intron 3 Intronic c.377-9T>G p.? Suspected Pathogenic Legius syndrome Van Minkelen  
Intron 3 Splice Site c.377-2A>C p.Cys127Lysfs*2 Pathogenic Legius syndrome Brems (2012)
Acceptor splice site is affected; r.377_423del.
Exon 4 Nonsense c.381C>A p.Cys127* Pathogenic Legius syndrome Pasamant
Familiy history of multiple CALMs
Exon 4 Nonsense c.389C>A p.Ser130* Pathogenic Legius syndrome Pasamant
Family history of multiple CALMS, mutation tracks with the disease in family
Exon 4 Nonsense c.389C>G p.Ser130* Pathogenic Legius syndrome Pasmant (2014)  
Exon 4 Frameshift c.395dupA p.Asn132Lysfs*2 Pathogenic Legius syndrome, with typical CALMs, axillary freckling, learning disabilities. B-cell acute lymphoblastic leukaemia Pasmant (2014)
Reported c.395dupA p.Asn133fs. Patient 11.2 y/o, female. B-ALL(B-cell acute lymphoblastic leukaemia) with osterolytic lesions. BM cell karyotype: 46,Ss[30]/45,XX,der(5),del(15),(q11q25),-20[3].
Intron 4 Splice Site c.423+1G>A p.Cys127Lysfs*2 Uncertain Multiple CALMs, varying degrees of freckling, head circumference percentile ranged from 50-97 and learning difficulty. Brems (2007)
Other findings: mild supravalvular pulmonic stenosis and mild pectus excavatum; one family member was previously diagnosed with Noonan syndrome. Splice mutation in the canoical GT splice donor site of intron 5 causes skipping of exon 5 and out of frame deletion of 47 nucleotides at the mRNA level. r.377_4233del (Brems 2012).
Intron 4 Splice Site c.423+5G>A c.Cys124Glnfs*10 Pathogenic Legius syndrome Messiaen
r.378_423+1del
Intron 4 Intronic c.424-8C>A p.? Benign Muram-Zborovski (2010)
High frequency in the population. rs7180446. NHLBI Exome Sequencing Project minor allele frequency: AA 31.41%, EA 10.31%. This variant was never found as an isolated event but as a haplotype involving c.291A>G, c.1044C>T and/or c.424-98C>T; this variant is not predicted to cause splice-site alteration.
Exon 5 Synonymous c.426A>G p.= Uncertain Messiaen
May have segmental NF
Exon 5 Missense c.446G>A p.Ser149Asn Benign Multiple CALMs (Brems and Messiaen). Brems (2007)
rs373384814. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%. Patient did not meet NF1 criteria. Rare, probablyBenign variant: Elk-reporter assay: WT, PC12-assay: WT, not evolutionarily conserved, SIFT: tolerated, PolyPhen:Benign, pathogenicity not supported by family studies (Messiaen 2009). Classified asBenign (Brems 2013).
Exon 5 Frameshift c.460_463dupGATC p.His155Argfs*13 Pathogenic Brems (2012)  
Exon 5 Frameshift c.468_469insGA p.Phe157Aspfs*18 Pathogenic Multiple CALMs. Spencer (2011)  
Exon 5 Frameshift c.468_469insCA p.Phe157fs Pathogenic Multiple CALMs. Messiaen (2009)
eFigure 1.
Exon 5 Nonsense c.475C>T p.Gln159* Pathogenic Brems (2012)  
Exon 5 Deletion c.493delA p.Ser165Valfs*9 Pathogenic Multiple CALMs. Spencer (2011)  
Exon 5 Missense c.511T>C p.Ser171Pro Uncertain Messiaen
rs376527959. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.02%.
Exon 5 Missense c.525G>A p.Glu179Lys Uncertain
rs143121426. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 5 Missense c.563T>C p.Met188Thr Uncertain
rs370735097. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 5 Missense c.564G>A p.Met188Ile Benign Multiple CALMs. Messiaen (2009)
Patient did not meet NF1 criteria. ProbablyBenign: Elk-reporter assay: WT, PC12-assay: WT, not evolutionarily conserved, SIFT: tolerated, PolyPhen: benign, no family studies available; found in and individual with no clincial signs. Classified as benign (Brems 2013).
Exon 5 Frameshift c.576_580dupCAATC p.Gln194Profs*4 Pathogenic Multiple CALMs, axillary freckling and mild learning disability. Denayer (2010)
Met NF1 criteria. Other findings: maxillary and malar hypoplasia, prognathism, down-slanting palpebral fissures, Noonan facies, pectus excavatum, low set ears, high narrow palate; also found Chaiari 1 malformation with syringomyelia with secondary scoliosis, normal echocardiogram and thoracic scoliosis requiring surgery.
Exon 5 Nonsense c.580C>T p.Gln194* Pathogenic Multiple CALMs, axillary and inguinal freckling, learning disabilities and head circumference: greater than 98th percentile. Muram-Zborovski (2010)
Patient met NF1 criteria. Clinical diagnosis of NF1. Altered pigmentation without tumorigenesis.
Exon 6-7 Deletion c.583-2841-?_c.*80+?del p.? Pathogenic Legius syndrome Messiaen
Mild scoliosis.
Intron 5 Intronic c.583-7A>G p.? Benign
High frequency in population. rs115970207. NHLBI Exome Sequencing Project minor allele frequency: AA 2.32%, EA 0.00%.
Exon 6 Missense c.587C>T p.Thr196Ile Benign Multiple CALMs (Spencer). Multiple CALMs and abnormal development (Messiaen). Messiaen (2009)
rs147474792. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.06%. Did not meet NF1 criteria. ProbablyBenign: Elk-reporter assay: WT, PC12-assay: WT, not evolutionarily conserved, SIFT: tolerated, PolyPhen:Benign, family studies not available (Messiaen 2009). Also reported in Spencer 2011. Classified asBenign (Brems 2013).
Exon 6 Nonsense c.605T>A p.Leu202* Pathogenic Multiple CALMs. Messiaen (2009)
Patient did not meet NF1 criteria. De novo mutation, mother has 1 CALM.
Exon 6 Missense c.607G>A p.Asp203Asn Uncertain
rs139897054. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 6 Synonymous c.619A>C p.= Benign
rs368660900. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 6 Synonymous c.633C>T p.= Benign
rs149991304. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 6 Missense c.634G>A p.Val212Ile Uncertain Multiple CALMs. Spencer (2011)
Family and functional studies needed to assess pathogenicity.
Exon 6 Nonsense c.637C>T p.Gln213* Pathogenic Multiple CALMs, axillary and inguinal freckling and learning disability. Pasmant (2009)
NF1 clinical diagnosis. Mutation tracked with the disease. Other findings: epilepsy.
Exon 6 Missense c.640C>T p.Arg214Trp Uncertain
rs376699107. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 6 Missense c.643C>G p.Gln215Glu Uncertain
rs121434314. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 6 Nonsense c.643C>T p.Gln215* Pathogenic Multiple CALMs and lipomas. Brems (2007)
Other findings: one family member also had Wilms tumor, tubular colonadenoma and paroxysmal atrial tachycardia.
Exon 6 Missense c.645A>C p.Gln215His Uncertain
rs144227155. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 6 Missense c.667delC p.Leu223* Pathogenic Multiple CALMs. Spencer (2011)  
Exon 6 Frameshift c.673delT p.Ser225Profs*7 Pathogenic Messiaen  
Exon 6 Missense c.674C>T p.Ser225Phe Uncertain No signs of Legius syndrome; has B-cell acute lymphoblastic leukaemia Pasmant (2014)
Male, 3.8 y/o, B-ALL (B-cell acute lymphoblastic leukaemia), BM cell karyotype: 46, XY. Tel-AML1 fusion associated molecular lesions. Patient had no typical cutaneous symptoms of Legius syndrome and no NF2 characteristic complications.
Exon 6 Synonymous c.675C>T p.= Benign Messiaen
rs144764225. NHLBI Exome Sequencing Project minor allele frequency: AA 0.05%, EA 0.10%.
Intron 6 Intronic c.685-15C>G p.? Uncertain
rs369834749. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Intron 6 Intronic c.685-7T>C p.? Uncertain
rs371620589. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 7 Synonymous c.687C>A p.= Uncertain
rs376226762. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 7 Missense c.698C>A p.Ser233* Pathogenic Legius syndrome Messiaen
Family history.
Exon 7 Frameshift c.700dupA p.Ile234Asnfs*9 Pathogenic Not given Leiden Database (LOVD)  
Exon 7 Frameshift c.700_703delATCA p.Ile234Aspfs*14 Pathogenic Multiple CALMs and head circumference: greater than 95th percentile. Messiaen (2009)
Patient did not meet NF1 criteria. Mutation was de novo and there was no LS signs in parents.
Exon 7 Missense c.702C>G p.Ile243Met Uncertain
rs138553244. NHLBI Exome Sequencing Project minor allele frequency: AA 0.23%, EA 0.00%.
Exon 7 Missense c.767G>A p.Arg256His Uncertain Five month old with CALMs and hypopigmentation (database submission). Brems (2012)
Legius syndrome (Brems 2012). Found in an unaffected father (database submission). Characterized as unclassified (Brems 2013).
Exon 7 Missense c.769C>T p.Arg257Cys Uncertain Legius syndrome Brems (2012)
Legius syndrome. Unclassified (Brems 2013).
Exon 7 Frameshift c.781delT p.? Pathogenic Multiple CALMs and Crowe sign. Lopez (2011)
Histopathologic examination showed basal hyperpigmentation without an increase in melanocytes. After 4 years there has not been additional cutaneous or extracutaneous features.
Exon 7 Nonsense c.784A>T p.Arg262* Pathogenic Multiple CALMs, axillary and inguinal freckling. Spurlock (2009)
Patient met NF1 criteria. Other findings: inguinal haemangioma.
Exon 7 Frameshift c.796_797delAT p.Met266Valfs*4 Pathogenic Multiple CALMs. Brems (2007)
Did not meet NF1 criteria. Family history of CALMs.
Exon 7 Missense c.821A>G p.Asp274Gly SuspectedBenign Brems (2012)
rs111363743
Exon 7 Frameshift c.832dupT p.Ser278Phefs*7 Pathogenic Brems (2012)  
Exon 7 Missense c.866A>C p.Lys289Thr Uncertain
rs372665535. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 7 Frameshift c.923_924delCT p.Ser308Cysfs*4 Pathogenic Multiple CALMs, head circumference: 25-50th and 97th percentile. Messiaen (2009)
Patient did not meet NF1 criteria.
Exon 7 Missense c.926T>C p.Val309Ala Benign Multiple CALMs. Spencer (2011)
rs114636635. NHLBI Exome Sequencing Project minor allele frequency: AA 0.66%, EA 0.00%.Benign (Brems 2013).
Exon 7 Missense c.931T>C p.Phe311Leu Uncertain Messiaen
rs375700452. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 7 Missense c.938C>T p.Thr313Met Benign Multiple CALMs. Messiaen (2009)
Patient did not meet NF1 criteria. Other findings: cortical cysts. ProbablyBenign: Elk-reporter assay: WT, PC12-assay: WT, not evolutionarily conserved, (Messiaen 2009). Benign (Brems 2013).
Exon 7 Synonymous c.939G>A p.= Benign
rs140644874. NHLBI Exome Sequencing Project minor allele frequency: AA 0.05%, EA 0.05%.
Exon 7 Nonsense c.940C>T p.Gln314* Pathogenic Multiple CALMs, axillary and inguinal freckling, macrocephaly and mild learning disability. Denayer (2010)
Patient met NF1 criteria. Other findings: hypertelorism, broad nasal bridge, small nose tip, large mouth with thick underlip, upslanting palpebral fissures; also found congenital scoliosis, block vertebra L4-L5, sensorineural hearing loss, frequent headaches, brain MRI: white matter lesions frontal and temporo-occipital T2 hyperintense.
Exon 7 Missense c.944C>T p.Pro315Leu SuspectedBenign Brems (2012)
rs115440602. NHLBI Exome Sequencing Project minor allele frequency: AA 0.16%, EA 0.00%.
Exon 7 Synonymous c.963G>A p.= Benign
rs369711772. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.03%.
Exon 7 Nonsense c.964A>T p.Lys322* Pathogenic Multiple CALMs, head circumferences: greater than 97th, 97th and 90-97th percentile (Messiaen 2009). Brems (2007)
Other findings: One family member with suspected Noonan syndrome and mild speech delay, down-slanting palpebral fissures, short neck, distal pectus excavatum where PTPN11 and PTEN testing was negative; individuals did not met NF1 criteria (Messiaen 2009).
Exon 7 Nonsense c.973C>T p.Arg325* Pathogenic Multiple CALMs and family history or CALMS (Brems). Multiple CALMs, axillary and inguinal freckling, head circumferences: 10th, 25-50th percentile, abnormal development: special education and ADHD and language delay (Messian). Brems (2007)
Other findings: dermoid tumor in left ovary; found in two families that also met NF1 criteria (Messiaen 2009).
Exon 7 Frameshift c.989delG p.Gly330Valfs*76 Pathogenic Brems (2012)  
Exon 7 Nonsense c.991G>T p.Glu331* Pathogenic Multiple CALMs. Spencer (2011)  
Exon 7 Missense c.1001G>A p.Arg334His Uncertain
rs146702985. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 7 Missense c.1006G>A p.Val336Ile Uncertain
rs373477920. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 7 Missense c.1031A>G p.His344Arg Uncertain Multiple CALMs. Spencer (2011)
rs376679136. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%. Family and functional studies needed to assess pathogenicity. Unclassified (Brems 2013).
Exon 7 Synonymous c.1044T>C p.Val348Val Benign Muram-Zborovski (2010)
High frequency in population. rs3751526. NHLBI Exome Sequencing Project minor allele frequency: AA 31.43%, EA 10.31%. Muram-Zborovski 2010 reported that this variant was never found as an isolated event but as a haplotype involving c.291A>G, c.424-8A>C and/or c.424-98C>T.
Exon 7 Frameshift c.1045_1046delAG p.Arg349Glyfs*11 Pathogenic Multiple CALMs, general and inguinal freckling, macrocephaly, suspected autism. Denayer (2010)
Patient did not meet NF1 criteria.
Exon 7 Frameshift c.1048_1049delGG p.Gly350Lysfs*10 Pathogenic Multiple CALMs and freckling. Spurlock (2009)
Patient met NF1 criteria. Other findings: excessive periorbital pigmentation.
Exon 7 Frameshift c.1048_1060del p.Gly350Metfs*52 Pathogenic Multiple CALMs, diffuse freckling (Pasamant). Multiple CALMs, macrocephaly, ADHD and lipomas (Denayer). Pasmant (2009)
Other findings: hypertelorism, ptosis, low implanted posteriorly rotated ears, widely spaced nipples, pectus excavatum, laryngomalacia and cubitus valgus (Denayer 2010). Clinical diagnosis of NF1 (Pasmant 2009).
Exon 7 Frameshift c.1149_1152delAGAG p.Gly350Aspfs*55 Pathogenic Multiple CALMs (Brems). Multiple CALMs without freckling (Spurlock). Multiple CALMs, axillary and inguinal freckling, head circumferences: 90-97th and 50th percentile; also found, angiolipoma (Messiaen). Multiple CALMs, axillary and inguinal freckling (De Brems (2007)
Met NF1 criteria. Other findings: tenosynovial giant cell tumor localized type; also found in one patient NF1:c.2755delG with postaxial polydactyly hands/feet and anal stenosis (Messiaen 2009); unilateral vestibular schwannoma after age 50, brain MRI: asymptomatic arachnoid cyst right temporal lobe (Denayer 2010). Also reported in Spencer 2010.
Exon 7 Missense c.1078A>G p.Lys360Glu Uncertain
rs374685699. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 7 Frameshift c.1073delC p.Pro358Leufs*48 Pathogenic Multiple CALMs. Spencer (2011)
Previously Reported (Brems 2013)
Exon 7 Missense c.1089G>A p.Ile363Met Uncertain No signs of Legius syndrome; has B-cell acute lymphoblastic leukaemia Pasmant (2014)
rs140225135. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%. Male, 10.8 y/o, had no typical cutaneous symptoms of Legius syndrome and no NF1 characteristic complicatons, B-cell acute lymphoblastic leukaemia, BM cells karyotype: 53-54, XY,+X[9], +5[7],+8[7],+12[3],+17[8],+18[8],+21[3],+21X2[6]. FLT3 hyperexpression associated molecular lesions. This mutation affects the C-termius SPROUTY-like (SPR) domains. rs140225135 (Pasmant 2014).
Exon 7 Missense c.1096G>A p.Val366Ile Uncertain
rs372623722. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 7 Deletion c.1155del p.Gly385Ile*20 Pathogenic Legius syndrome Brems (2013)
Reported in 9 individuals
Exon 7 Missense c.1192G>A p.Asp398Asn Benign Multiple CALMs (Spencer 2011). Multiple CALMs and hyperactivity (Messiaen). Messiaen (2009)
Other findings: macrosomia, pulmonic stenosis, hypertelorism, short narrow palpebral fissures, low posterior hairline, posteriorly rotated ears and short neck; found in sibling with one CALM and no other signs; half sibling with classic NF1 also carried this mutation (Messiaen 2009). Rare, probablyBenign variant: Elk-reporter assay: WT, PC12-assay: WT, not evolutionarily conserved, SIFT: tolerated, PolyPhen:Benign, pathogenicity not supported by family studies, did not meet NF1 criteria (Messiaen 2009). Also reported in Spencer 2011.Benign (Brems 2013).
Exon 7 Frameshift c.1204_1207dupTTGC p.Arg403Leufs*30 Pathogenic Multiple CALMs and head circumference 90th percentile. Messiaen (2009)
Patient did not meet NF1 criteria. De novo mutation with family history of multiple CALMs without SPRED1 or NF1 mutation.
Exon 7 Missense c.1222G>T p.Val408Leu Uncertain
rs150307819. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 7 Missense c.1223T>A p.Val408Glu Uncertain Brems (2012)
Legius syndrome. Unclassified (Brems 2013).
Exon 7 Missense c.1243C>G p.Pro415Ala Pathogenic Multiple CALMs, axillary pigmentation, head circumferences: 20th and 75th percentile, language delay and fine motor delay. Messiaen (2009)
Loss of function missense mutation: Elk-reporter assay: defect, PC12-assay: defect, evolutionarily conserved, SIFT: not tolerated, PolyPhen: probably damaging, pathogenicity supported by family studies, one person met NIH criteria and 1 person did not. Pathogenic (Brems 2013).
Exon 7 Missense c.1246C>T p.Cys416Arg Uncertain Multiple CALMs. Spencer (2011)
Family and functional studies needed to assess pathogenicity. Unclassified (Brems 2013).
Exon 7 Frameshift c.1248dupT p.Met417Tyrfs*15 Suspected Pathogenic Multiple CALMs and inguinal freckling. Messiaen (2009)
Patient did not meet NF1 criteria. Other findings: seizures.
Exon 7 frameshift c.1252delT p.Cys418Alafs*6 Pathogenic Multiple CALMs (Spencer). Multiple CALMs, axillary and inguinal freckling, head circumferences: much greater than 97th and 90-95th percentile, language delay and developmental delay, seizures and one patient with unequal gluteal folds (Messiaen). Messiaen (2009)
Patient met NF1 criteria. Other findings: seizures and one patient with unequal gluteal folds (Messiaen 2009). Also reported in Spencer 2011.
Exon 7 Synonymous c.1260C>T p.= Benign
rs202087411. NHLBI Exome Sequencing Project minor allele frequency: AA 0.02%, EA 0.00%.
Exon 7 Missense c.1273A>G p.Met425Val Uncertain Legius syndrome Brems (2012)
rs368307475. NHLBI Exome Sequencing Project minor allele frequency: AA 0.05%, EA 0.00%. Unclassified (Brems 2013).
Exon 7 Missense c.1283G>A p.Arg428His Uncertain
rs369492789. NHLBI Exome Sequencing Project minor allele frequency: AA 0.00%, EA 0.01%.
Exon 7 Missense c.1289G>C p.Gly430Ala Uncertain Brems (2012)
Unclassified (Brems 2013).
Exon 7 Frameshift c.1289_1298del p.Gly430Valfs*29 Uncertain Brems (2012)
Classified as uncertain by Brems 2012.
Exon 7 Missense c.1298G>A p.Cys433Tyr Benign Messiaen (2009)
Rare, probablyBenign variant: Elk-reporter assay: WT, PC12-assay: WT, evolutionarily conserved, SIFT: not tolerated, PolyPhen:Benign, pathogenicity not supported by family studies: found in an unaffected mother of a classic NF1 patient who also carried this variant (Messiaen 2009).Benign (Brems 2013).