BMPR2 Database

  • Reference sequences were NC_000002.11 and NM_001204.6. 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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270 variants found

Genomic Position Location ▾ Mutation Type Published As Nucleotide Change Protein Change Classification References Comments
5'UTR Deletion/Insertion c.*-944/5GC-AT c.-944_-943delinsAT p.? Pathogenic Aldred (2007)
Results in a novel start codon and the mutation segregated with the disease, not found in 400 ethnically matched controls.
5' UTR 5' UTR substitution c.G-669A c.-669G>A p.? Pathogenic Wang (2009)
Age at diagnosis 36, this mutation abolished a potential specificity protein 3 transcription factor-binding site and a dual luciferase assay showed that the promoter carrying this variant allele had significantly decreased transcriptional activity compared with the -669G allele. Similar findings by (Li 2009). rs115604088: minor allele frequency 0.008 (1000 Genomes) and 0.017 (CEU).
Exon 01-13 Deletion c.1-?_3117-?del ex1-13del p.0? Pathogenic Aldred (2006)
ID: 21646, complete null, confirmed de novo, deletion extended into the 5' region (Aldred 2006). Patient 68 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 01-3 Deletion deletion ex1-3 ex1-3del p.? Pathogenic Girerd (2010)
Reported once.
Exon 01 Deletion c.?_IVS1del ex1del p.0? Pathogenic Machado (2001)
Family UKSp15: 31 years old at disease onset, Exon 01 and 12 analyzed for dosage; Family: UK01: eight affected individuals in the same family, age at disease onset for this family ranged from 1-42, Exon 01 and 12 analyzed for dosage (Machado 2001). ID: 3577 & ID:20801: predicted consequence: Altered translation start site or promoter deletion/complete null (Aldred 2006). Family 30 & 110: MLPA analysis showed a deletion of Exon 01; transcript was subject to nonsense mediated decay (Cogan 2006).
Exon 01-4 Deletion del Exon 01-4 ex1-4del p.? Pathogenic Sztrymf (2008)
Patient 64 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 01 Frameshift c.9_10dup p.Leu5fs Pathogenic Smith (unpublished)
Found in a patient with no family history of PAH, internal case.
Exon 01 Frameshift c.15_19delGCAGC c.15_19del p.Gln6fs Pathogenic Morisaki (2004)
Case 1: patient was 31 years old at time of study.
Exon 01 Frameshift c.21_29delGCCCTGGCG
insA
c.21_29delinsA p.Pro8fs Pathogenic Machado (2006)  
Exon 01 Nonsense c.27G>A c.27G>A p.Trp9X Pathogenic Machado (2006)  
Exon 01 Missense c.28C>T c.28C>T p.Arg10Trp Uncertain Baloira (2008)
Age of onset: 72 years, published protein change was p.T10W; no family history of PAH.
Exon 01 Nonsense c.39G>A p.Trp13X Pathogenic Hamid (2010)
Transcript escaped nonsense mediated decay, cultured lymphocytes contained detectable levels of the mutant transcript by translational re-initiation at a downstream Kozak sequence resulting in the omission of 173 amino acids; disease presentation at age 56 with family history; sequence published TGCCCTGG/ACTACCAT.
Exon 01 Frameshift c.44delC c.44del p.Pro15fs Pathogenic Machado (2001)
Family US70: two affected individuals in this family, age of disease onset ranged from 36-38 (Machado 2001). Reported in patient with pulmonary veno-occlusive disease, 36 years old at diagnosis, the truncated protein is predicted to contain only a segment of the extracellular domain and is therefore unlikely to be expressed on the cell surface, also found in an unaffected sibling (Runo 2003). Patient had pulmonary veno-occlusive disease (Machado 2006).
Exon 01 Nonsense c.47G>A c.47G>A p.Trp16X Pathogenic Harrison (2004)
Patient 21140: diagnosis of PAH at 6 year of age, the mutant transcript was expected to be subject to nonsense mediated decay, mutation was de novo.
Exon 01 Nonsense c.48G>A c.48G>A p.Trp16X Pathogenic Sztrymf (2008)
Patients 1 and 2 in (Sztrymf 2008). Also reported twice in (Girerd 2010).
Exon 01 Frameshift c.51-814 del c.51_814del p.Ile18fs Pathogenic Machado (2001)
Family UKsp14: 26 years old at age of onset; RT-PCR using mRNA isolated from whole-lung tissue yielded a PCR product deleted for nucleotides 51-814 encompassing the last 26 nucleotides of Exon 01, all of exons 2-5, and two-thirds of Exon 06.
Intron 01 Splice site c.76+2T>C p.? Pathogenic Smith (unpublished)
Found in a patient with a family history of PAH, internal case.
Intron 01 Intronic c.76+35delC p.? Uncertain dbSNP
rs34040645
Exon 02-13 Deletion c.77-?_3117-?del ex02-13del p.? Pathogenic Aldred (2006)
ID: 21016; functional null; confirmed in affected sibling, Exon 01 encodes a 25 amino acid leader sequence and deletion results in a complete null (Aldred 2006). Family 57: MLPA analysis showed deletions of Exon 02-13, transcript was subject to nonsense mediate decay (Cogan 2006).
Exon 02 Deletion IVS1_IVS2del ex02del p.? Pathogenic Cogan (2006)
Family 12 and 108: MLPA analysis showed a deletion of Exon 02, predicted to result in an in-frame loss of amino acids 26-82, transcript was subject to nonsense mediated decay (Cogan 2006). Predicted consequence: In-frame deletion of 57 amino acids, extracellular ligand binding domain. ID: 5196. ID: 6224: peripheral occlusive vascular disease, RNA from lung tissue: exons 1 and 4 were amplified and sequenced, confirming deletion of Exon 02. Also reported in (Girerd 2010).
Exon 02-03 Deletion del Exon 02-3 ex02-03del p.? Pathogenic Rosenzweig (2008)
Patient 21: age 2, no family history of PAH (Rosenzweig 2008). Found in a patient with no family history of PAH, internal case (Smith unpublished).
Exon 02 Duplication IVS1_IVS2dup ex02dup p.? Pathogenic Cogan (2006)
Family 65: MLPA analysis showed a duplication of Exon 02, predicted to result in an in-frame duplication of amino acids 26-82, transcript was subject to nonsense mediated decay.
Exon 02 Synonymous c.84G>A c.84G>A p.= Benign Wang (2010)
Classified as a polymorphism with a frequency 1/76 in a Chinese cohort.
Exon 02 Missense c.86A>G p.Asn29Ser Uncertain dbSNP
rs112862820. Average heterozygosity: 0.005, chromosome count: 4532.
Exon 02 Nonsense c.91G>T c.91G>T p.Glu31X Pathogenic Koehler (2004)
Patient ID K4518A: also found in unaffected parent.
Exon 02 Missense c.100T>C c.100T>C p.Cys34Arg Suspected Pathogenic Machado (2006)
Found in a patient with a family history of PAH.
Exon 02 Frameshift c.116delC c.116del p.Pro39fs Pathogenic Rosenzweig (2008)
Patient 21: age 30, no family history of PAH.
Exon 02 Nonsense c.120T>G c.120T>G p.Tyr40X Pathogenic Machado (2006)
Patient also has pulmonary veno-occlusive disease.
Exon 02 Nonsense c.124C>T c.124C>T p.Gln42X Pathogenic Fujiwara (2008)
Proband 17: symptom onset at age 14.
Exon 02 Missense c.125A>G c.125A>G p.Gln42Arg Suspected Pathogenic Roberts (2004)
Adult 1: patient's age was 19 at initial catheterization, PAH diagnosis at age 1, patient also had down syndrome, and a congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.
Exon 02 Missense c.140G>A c.140G>A p.Gly47Asp Suspected Pathogenic Roberts (2004)
Child 6: PAH diagnosis at 19 months and was reported to have congenital hearth defect: aortopulmonary window and ventricular septal defect; this variant was not found in 196 healthy controls or 1,000 other PAH cases.
Exon 02 Missense c.156-157delTC c.156_157del p.His53X Pathogenic Machado (2001)
Family US42: Three affected family members; age of disease onset ranged from 32-39.
Exon 02 Synonymous c.165T>C c.165T>C p.= Benign Morisaki (2004)
Polymorphism found in the general population with an allele frequency of 1.1% (Morisaki 2004). Classified as a polymorphism with a frequency of 1/76 in a Chinese cohort (Wang 2010). Polymorphism with a frequency of 1.1% (Machado 2006).
Exon 02 Frameshift c.166delG c.168del p.Thr57fs Pathogenic Machado (2006)  
Exon 02 Missense c.179G>A c.179G>A p.Cys60Tyr Suspected Pathogenic Thomson (2000)
Patient 1: paternal inheritance, not found in 150 normal control chromosomes.
Exon 02 In-frame deletion c.188-208del21 c.188_208del p.Ser64_Trp70del Pathogenic Machado (2006)
Pt 91: age 19 in (Elliott 2006). Also reported in (Machado 2006)
Exon 02 Missense c.196T>C c.196T>C p.Cys66Arg Pathogenic Cahn (2004)
Diagnosis at 26 years of age, the variant was also found in two unaffected family members (father and sister), family history of PAH, nucleotide position was found using the published sequence because the nucleotide position was reported as 604 (Cahn 2004). Also reported in (Wang 2009) and (Wang 2010).
Exon 02 Missense c.197G>A c.197G>A p.Cys66Tyr Pathogenic Machado (2006)
Patient 3 in (Sztrymf 2008). Reported twice in (Girerd 2010). Also reported in (Machado 2006).
Exon 02 Missense c.200A>G c.200A>G p.Tyr67Cys Pathogenic Morisaki (2004)
Case 2: patient was 33 years old at time of study (Morisaki 2004). Reported twice in (Machado 2006). Patient 4 in (Sztrymf 2008). Patient 1: age 33 in (Wang 2010). Reported twice in (Girerd 2010).
Exon 02 Nonsense c.201T>G c.201T>G p.Tyr67X Pathogenic Rosenzweig (2008)
Patient 9: age 41, family history of PAH.
Exon 02 Missense c.203G>A c.203G>A p.Gly68Asp Pathogenic Machado (2006)
Reported twice in (Machado 2006). Pt 60: age 46 in (Elliott 2006).
Exon 02 Nonsense c.218C>G c.218C>G p.Ser73X Pathogenic Lane (2000)
Family US35: not found in 214 chromosomes from healthy controls, this variant truncates the protein before the transmembrane domain and if translated may fail to reach the cell surface (Lane 2000). Pt 159: age 33 in (Elliott 2006).
Exon 02 Insertion c.241insT c.240_241insT p.Lys81X Pathogenic Johri (2010)
Patient age at disease presentation was 83 with a family history of PAH, A low level of aberrant mRNA was detected in the lymphocytes from this patient.
Exon 02 Nonsense c.244C>T c.244C>T p.Gln82X Pathogenic Rindermann (2003)
Family 4452 in (Rindermann 2003). Reported once in (Machado 2006).
Exon 02 Missense c.246A>C c.246A>C p.Gln82His Suspected Pathogenic Humbert (2002)
Patient had taken dexfenfluramine for 5 months, affected amino acid is in the extra cellular domain that is responsible for ligand binding and dimerization, not found in 130 healthy controls.
Exon 02 Missense c.247G>A c.247G>A p.Gly83Arg Pathogenic Sztrymf (2008)
Patient 5 in (Sztrymf 2008). Also reported in (Girerd 2010).
Intron 02 Splice site c.247+1delGCAAGTG c.247+1_247+7del p.? Pathogenic Rosenzweig (2008)
Patient 1: age 12, family history of PAH.
Intron 02 Splice site IVS2 247+2delC c.247+2del p.? Pathogenic Cogan (2006)
Family 76: splice-site mutation led to the loss of amino acids 63-82 and less commonly the loss of amino acids 47-82 from the use of an Exon 02 cryptic splice-site 108bp upstream, transcript was subject to nonsense mediated decay.
Intron 02 Intronic IVS2 247+6T>G c.247+6T>G p.? Pathogenic Cogan (2006)
Family 68: this alteration resulted in alternative use of two upstream GT cryptic donor sites located within Exon 02. One mutant species resulted from us on an Exon 02 cryptic splice site 108bp upstream resulting in loss of amino acids 63-82 and the other mutant species resulted from use of a second Exon 02 cryptic splice site 108 bp upstream resulting in loss of amino acids 47-82, transcript was subject to nonsense mediated decay.
Exon 03 Insertion/Deletion c.-5-248delTATAGGinsAC c.248-5_248delinsAC p.? Pathogenic Rosenzweig (2008)
Patient 3: age 5, family history of PAH.
Exon 03 Deletion IVS2_IVS3_del ex03del p.? Pathogenic Cogan (2006)
Family 92 and 95: MLPA analysis showed a deletion of Exon 03, predicted to result in an in-frame loss of amino acids 83-139, transcript was subject to nonsense mediated decay (Cogan 2006). Found in a patient with no family history of PAH, internal case (Smith unpublished).
Intron 02 Splice site c.248-1G>A c.248-1G>A p.? Pathogenic Machado (2006)
Splice defect, this substitution is located in the acceptor splice site of intron 2 (Machado 2006). Also reported in (Sztrymf 2008) and (Girerd 2010).
Exon 03 Nonsense c.255G>A c.255G>A p.Trp85X Pathogenic Machado (2006)
Patient 6 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).
Exon 03 Nonsense c.274C>T c.274C>T p.Gln92X Pathogenic Machado (2006)
Patient 7 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).
Exon 03 Missense c.276A>C c.276A>C p.Gln92His Benign Machado (2006)
Polymorphism with a frequency of 1.1%.
Exon 03 Frameshift c.277insG c.277dup p.Glu93fs Pathogenic Cogan (2006)
Pt 303: transcript was subject to nonsense mediated decay.
Exon 03 Missense c.280T>C c.280T>C p.Cys94Arg Pathogenic Machado (2006)
Patient 8 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).
Exon 03 Nonsense c.292G>T c.292G>T p.Glu98X Pathogenic Wang (2009)
Reported once, age: 34, no family history of PAH (Wang 2009 and 2010).
Exon 03 Missense c.292G>A c.292G>A p.Glu98Lys Suspected Pathogenic Wang (2010)
Patient 2: age 34; no family history of PAH.
Exon 03 Missense c.295T>C c.295T>C p.Cys99Arg Pathogenic Machado (2006)
Pt 113: age 38 in (Elliott 2006). Patient 4: age 14, family history of PAH in (Rosenzweig 2008). Also reported twice in (Machado 2006).
Exon 03 Missense c.304A>G c.304A>G p.Thr102Ala Suspected Pathogenic Roberts (2004)
Adult 2: PAH diagnosis at 16 years and was reported to have congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.
Exon 03 Missense c.319T>C c.319T>C p.Ser107Pro Suspected Pathogenic Roberts (2004)
Adult 3: PAH diagnosis at 5 years, congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.
Exon 03 Nonsense c.320C>G c.320C>G p.Ser107X Pathogenic Sztrymf (2008)
Patient 9 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 03 Nonsense c.339C>G c.339C>G p.Tyr113X Pathogenic Fujiwara (2008)
Proband 10: symptoms started at age 9, de novo mutation.
Exon 03 Nonsense c.339C>A c.339C>A p.Tyr113X Pathogenic Sztrymf (2008)
Patient 10 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 03 Missense c.350G>C c.350G>C p.Cys117Ser Pathogenic Machado (2006)
Patient 11 in (Sztrymf 2008). Also reported in (Girerd 2010) and (Machado 2006).
Exon 03 Missense c.350G>A c.350G>A p.Cys117Tyr Pathogenic Thomson (2000)
Patient 2: paternal inheritance, not found in 150 normal control chromosomes (Thomson 2000). Pt 7: age 32 in (Elliott 2006). Found in a patient with a family history of PAH, internal case (Smith, unpublished).
Exon 03 Missense c.353G>A c.353G>A p.Cys118Tyr Suspected Pathogenic Machado (2006)
No family history of PAH.
Exon 03 Missense c.354T>G c.354T>G p.Cys118Trp Suspected Pathogenic Lane (2000)
Family US14: not found in 214 chromosomes from healthy controls, extracellular domain affected, predicted to perturb ligand binding (Lane 2000). Family study of affected and unaffected carriers showed altered protein expression between the two groups; differences highlight proteins that may be involved in the mechanism(s) that differentiates those individuals with a mutation that developed disease (Meyrick 2008).
Exon 03 Frameshift c.355delA c.355del p.Ser119fs Pathogenic Lane (2000)
Family UK13: not found in 214 chromosomes from healthy controls, this variant truncates the protein before the transmembrane domain and if translated may fail to reach the cell surface (Lane 2000). Diagnosis at 6 years old (Atkinson 2002).
Exon 03 Frameshift c.359_360delCA 359_360del p.Thr120fs Pathogenic Machado (2006)  
Exon 03 Missense c.367T>A c.367T>A p.Cys123Ser Pathogenic Machado (2001)
Family NOR01: five affected family members.
Exon 03 Missense c.367T>C c.367T>C p.Cys123Arg Pathogenic Machado (2001)
Family UK09: two affected family members, age at disease onset ranged from 9-26 (Machado 2001). Proband 7: onset of symptoms at age 9, ligand binding domain (Fujiwara 2008). Also reported in (Girerd 2010).
Exon 03 Missense c.370A>G c.370A>G p.Asn124Asp Pathogenic Sztrymf (2008)
Patient 12 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 03 Frameshift c.371dup c.371dup p.Asn124fs Pathogenic Girerd (2010)
Predicted to escape nonsense mediated decay.
Exon 03 Missense c.377A>G c.377A>G p.Asn126Ser Pathogenic Girerd (2010)
Reported twice.
Exon 03 Frameshift c.407_408del c.407_408del p.Thr136fs Pathogenic Girerd (2010)  
Exon 03 Frameshift c.408_412delAACAC c.408_412del p.Pro138fs Pathogenic Girerd (2010)  
Intron 03 Deletion/Insertion c.418+2_418+4TAA>GAG c.418+2_418+4
delinsGAG
p.? Pathogenic Morisaki (2004)
Case 3: patient was 19 years old at time of study, inactivates splice donor site, absent in both parents.
Intron 03 Splice site c.418+3A>T c.418+3A>T p.? Pathogenic Machado (2006)
Splice defect detected in Patient 58, 59, and 60 (Sztrymf 2008). Reported 3 times in (Girerd 2010). Also reported in (Machado 2006).
Intron 03 Intronic c.418+5G>A c.418+5G>A p.? Pathogenic Rosenzweig (2008)
Patient 10: age 46; splice defect, family history of PAH.
Intron 03 Intronic c.420-38delT c.419-38del p.? Benign Machado (2006)
Polymorphism with a frequency of 13.8% (Machado 2006). Found with c.529+64C>T; frequency in PAH 15%; 20% frequency in chronic thromboembolic pulmonary hypertension and in 17% of controls (Ulrich 2009). rs34006388.
Exon 04-05 Deletion ex04-05del p.? Pathogenic Cogan (2005)
Pt 20: RT-PCR studies showed a deletion of Exon 04 and 5, this causes a frameshift that leads to a premature stop codon in Exon 06 nucleotides 33-35 (Cogan 2005). MLPA analysis (family 20) showed a deletion of Exon 04 and 5, out-of-frame deletion beginning at codon 140 with a PTC at codon 151, mutant transcripts were not detected in RNA and were subject to nonsense mediated decay (Cogan 2006). Patient 13: age 60, family history of PAH (Rosenzweig 2008).
Exon 04-08 Duplication dup ex4-8 ex04-08dup p.? Pathogenic Girerd (2010)  
Exon 04 Deletion ex04del p.? Pathogenic Smith (unpublished)
Found in a patient with a family history of PAH, internal case.
Exon 04-07 Deletion ex04-07del p.? Pathogenic Smith (unpublished)
Found in a patient with a family history of PAH, internal case.
Exon 04 Nonsense c.439C>T c.439C>T p.Arg147X Pathogenic Machado (2001)
Family US37: three affected family members, age at disease onset ranged from 10-39 (Machado 2001). Case 4: patient was 32 years old at time of study (Morisaki 2004). Reported 3 times in (Machado 2006). Patient 11: age 30, family history of PAH in (Rosenzweig 2008). Patient 13 and 14 in (Sztrymf 2008). Patient 3: age 18, no family history of PAH in (Wang 2010). Pt 30: age 34 in (Elliott 2006). Reported 4 times in (Girerd 2010).
Exon 04 Frameshift c.449dup c.449dup p.Ile151fs Pathogenic Girerd (2010)  
Exon 04 Frameshift 504insT (504_505insT) c.505dup p.Cys169fs Pathogenic Machado (2001)
Family UK21: two affected family members, age at onset ranged from 13-19.
Exon 04 Nonsense c.507-510delCTTTinsAAA c.507_510delinsAAA p.Cys169X Pathogenic Deng (2000)
Family PPH017: transmembrane domain, not found in 196 chromosomes (Deng 2000). Patient 12: age 48, family history of PAH (Rosenzweig 2008).
Exon 04 Nonsense c.507C>A c.507C>A p.Cys169X Pathogenic Machado (2006)  
Exon 04 Nonsense c.516C>G c.516C>G p.Tyr172X Pathogenic Cogan (2006)
Family 71: transcript was subject to nonsense mediated decay.
Exon 04 Frameshift c.528delA c.528del p.Gly177fs Pathogenic Girerd (2010)
Reported twice.
Exon 05-07 Deletion c.530-?_967+?del ex05-07del p.? Pathogenic Harrison (2004)
Patient 7913: diagnosis of PAH at 4 years of age, predicted mutant transcript would have Exon 04 spliced directly to Exon 08 and confirmed by RT-PCR, deletion of amino acids in the kinase domain, mutation was de novo (Harrison 2004). ID: 7913; Predicted consequence: In-frame deletion of 146 amino acids, kinase domain; confirmed de novo; pediatric (Aldred 2006).
Exon 05 Missense c.545G>A c.545G>A p.Gly182Asp Suspected Pathogenic Humbert (2002)
Patient had taken fenfluramine for 2 months, affected amino acid is in the Kinase domain, not found in 130 healthy controls. Functional studies have suggested that p.Gly182Asp variant protein induces a transcriptional response following BMP4 stimulation in a manner indistinguishable from wild type BMPR2, although statistical analyses supporting this conclusion were not performed (Nasim 2008)
Exon 05 Frameshift c.551_573del c.551_573del p.His184fs Pathogenic Sztrymf (2008)
Patient 15 (Sztrymf 2008). Reported once, predicted to escape nonsense mediated decay (Girerd 2010).
Exon 05 Missense c.556A>G c.556A>G p.Met186Val Suspected Pathogenic Roberts (2004)
Child 4: PAH diagnosis at 3 years and was reported to have ring chromosome 14 syndrome and congenital heart defect: complete atrial ventricular canal defect type C; this variant was not found in 196 healthy controls or 1,000 other PAH cases.
Exon 05 Nonsense c.583G>T c.583G>T p.Glu195X Pathogenic Sztrymf (2008)
Patient 17.
Exon 05 Synonymous c.600A>C c.600A>C p.= Benign Sankelo (2005)
Allele frequency of 5% among patients and 11% among controls (Sankelo 2005). Identified in 4 unrelated patients (Elliott 2006). Polymorphism with a frequency of 2.4% (Machado 2006). Frequency in PAH of 20% and 4% of controls (Ulrich 2009). Found in 8/90 patient samples, 8.8% (Smith unpublished). rs55722784
Exon 05 Missense c.604A>T c.604A>T p.Asn202Tyr Suspected Pathogenic Sztrymf (2008)
Patient 16, study included 223 patients.
Exon 05 Frameshift c.608-609delTG c.608_609del p.Leu203fs Pathogenic Wang (2009)
Reported in a single patient, age 20 in (Wang 2009 and 2010).
Exon 05 Frameshift c.612delA c.612del p.Lys204fs Pathogenic Sztrymf (2008)
Patient 18 in (Sztrymf 2008). Also reported in (Girerd 2010).
Intron 05 Intronic c.621+8T>C p.? Benign dbSNP
rs117575598
Intron 05 Intronic c.621+37C>G p.? Benign dbSNP
rs78779412
Intron 05 Intronic c.622-13A>T p.? Benign dbSNP
rs78796655
Exon 06 Deletion del ex6 ex06del p.? Pathogenic Girerd (2010)  
Exon 06 Nonsense c.631C>T c.631C>T p.Arg211X Pathogenic Thomson (2000)
Patient 3: not found in 150 normal control chromosomes (Thomson 2000). Family ITA01: two affected family members, age at disease onset ranged from 7-18 (Machado 2001). Found in two sisters who had taken dexfenfluramine for 1 - 2 months, not found in 130 healthy controls (Humbert 2002). Reported 5 times in (Machado 2006). mutational hotspot located in the kinase domain (Wong 2005). Identified in Patients 19, 20, 21, and 22 in (Sztrymf 2008). Family 66: transcript was subject to nonsense mediated decay (Cogan 2006). Pt 87: age 87 (Elliott 2006). Reported 6 times in (Girerd 2010). Reported once in (Portillo 2009).
Exon 06 Nonsense c.637C>T c.637C>T p.Arg213X Pathogenic Morisaki (2004)
Case 5 & 6: reported in two unrelated individuals, patient ages were 27 and 19 at the time of the study (Morisaki 2004). Pt 137: age 30; Pt 162: age 14 in (Elliott 2006). Found on the same allele as c.690-91delAGinsT and Family 64: transcript was subject to nonsense mediated decay, protein change was reported as R225C (Cogan 2006). Reported twice in (Machado 2006). Found in a patient without a family history of PAH, internal case (Smith, unpublished).
Exon 06 Frameshift c.659dupG c.659dup p.Ser221fs Pathogenic Machado (2006)  
Exon 06 Frameshift c.664_665delTTinsAAGG c.664_665delinsAAGG p.Leu222fs Pathogenic Machado (2006)  
Exon 06 Missense c.672G>T c.672G>T p.Glu224Asp Benign Machado (2001)
Found in individuals not at risk for the disease, found in 3 families in (Machado 2001). Polymorphism with a frequency of 3% (Machado 2006).
Exon 06 Frameshift c.689_690del c.689_690del p.Lys230fs Pathogenic Machado (2001)
Family US44: three affected family members, age at disease onset ranged from 4-46 in (Machado 2001). Patient 23 in (Sztrymf 2008). Reported once in (Girerd 2010).
Exon 06 Frameshift c.690-691delAGinsT c.690_691delinsT p.Lys230fs Pathogenic Deng (2000)
Family PPH022: kinase domain (Deng 2000). Family 64: found on the same allele as c.673C>T; transcript was subject to nonsense mediated decay (Cogan 2006). Patient 14: age 36, family history of PAH (Rosenzweig 2008).
Exon 06 Nonsense c.727G>T c.727G>T p.Glu243X Pathogenic Machado (2001)
Family FRA04: two affected family members both 40 years old at disease onset (Machado 2001). Pt 111: age 47 in (Elliott 2006). Reported once in (Machado 2006).
Exon 06 Missense c.727G>A c.727G>A p.Glu243Lys Suspected Pathogenic Wang (2010)
Patient 4: age 26, no family history of PAH.
Exon 06 Frameshift c.775delC c.775del p.Arg259fs Pathogenic Machado (2006)
Reported once in (Machado 2006). Patient 24 in (Sztrymf 2008). Reported once in (Girerd 2010).
Exon 06 Frameshift c.782_783del c.782_783del p.Ile261fs Pathogenic Girerd (2010)  
Exon 06 Frameshift c.787insT (786dupT) c.786dup p.Gly263fs Pathogenic Thomson (2000)
Patient 4: not found in 150 normal control chromosomes.
Exon 06 Frameshift c.790delG c.790del p.Asp264fs Pathogenic Machado (2006)  
Exon 06 Missense c.795G>T+c.796A>T c.795_796delinsTT p.Glu265_Arg266
delinsAsp265_X266
Pathogenic Smith (unpublished)
Found in a patient with a family history of PAH; variants may be on opposite chromosomes, internal case.
Exon 06 Frameshift c.796-799delAGAG c.796_799del p.Arg266fs Pathogenic Cogan (2006)
Family 135: transcript was subject to nonsense mediated decay.
Exon 06 Missense c.797G>C c.797G>C p.Arg266Thr Suspected Pathogenic Machado (2006)
No family history of PAH.
Exon 06 Frameshift c.802-803insA c.802dup p.Thr268fs Pathogenic Wang (2010)
Patient 5: age 16, family history of PAH, no family studies were reported.
Exon 06 Frameshift c.804delT c.804del p.Ala269fs Pathogenic Cogan (2006)
Family 124: transcript was subject to nonsense mediated decay.
Exon 06 Missense c.818T>G c.818T>G p.Met273Arg Suspected Benign Machado (2006)
Reported in a single patient in (Machado 2006). Frequency of 4% in control group; ESEfinder analysis: predicted to alternate the sequence of exonic splicing enhancers; RT-PCR analysis on the mRNA found that the mutation was also present in the transcript and did not influence the proper splicing (Ulrich 2009).
Exon 06 Missense c.830T>C c.830T>C p.Leu277Pro Pathogenic Sztrymf (2008)
Patient 25 in (Sztrymf 2008). Reported in a single patient in (Girerd 2010).
Intron 06 Splice site c.852+1G>A c.852+1G>A p.? Pathogenic Girerd (2010)
Splice defect.
Intron 06 Intronic c.853-22del p.? Benign dbSNP
rs11390605, rs66469476, rs11464745
Intron 06 Splice site c.853-2A>G c.853-2A>G p.? Pathogenic Machado (2006)
Patient 61: splice defect (Sztrymf 2008). Also reported in (Girerd 2010).
Intron 06 Splice site c.853-1G>C c.853-1G>C p.? Pathogenic Sztrymf (2008)
Patient 62: splice defect (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 07 Duplication 853-?_967+?dup ex07dup p.? Pathogenic Aldred (2006)
ID: 20046, predicted consequence: duplication of 38 amino acids, kinase domain; premature truncation within duplicated sequence.
Exon 07 Frameshift c.855delA c.855del p.Ser286fs Pathogenic Machado (2006)  
Exon 07 Nonsense c.860T>A c.860T>A p.Leu287X Pathogenic Machado (2006)  
Exon 07 Nonsense c.872delT c.872del p.Leu291X Pathogenic Cogan (2006)
Family 119: transcript was subject to nonsense mediated decay.
Exon 07 Missense c.901T>C c.901T>C p.Ser301Pro Pathogenic Machado (2006)
Reported once in (Machado 2006). Patient 26 and 27 in (Sztrymf 2008). Reported 3 times in (Girerd 2010).
Exon 07 Missense c.908G>A c.908G>A p.Arg303His Suspected Pathogenic Machado (2006)
Reported in a single patient, thromboembolic.
Exon 07 Nonsense c.928A>T c.928A>T p.Arg310X Pathogenic Sztrymf (2008)
Patient 28 in (Sztrymf 2008). Single patient, predicted to escape nonsense mediated decay (Girerd 2010).
Exon 07 Missense c.937G>C c.937G>C p.Ala313Pro Suspected Pathogenic Machado (2006)  
Exon 07 Nonsense c.961C>T c.961C>T p.Arg321X Pathogenic Koehler (2004)
Patient ID: K5429A in (Koehler 2004). Reported 3 times in (Machado 2006). Patient 15: age 39, family history of PAH in (Rosenzweig 2008). Patients 29, 30, and 21 in (Sztrymf 2008). Patient 6 and 7: ages 14 and 33 neither had a family history of PAH (Wang 2010). Reported 4 times, predicted to escape nonsense mediated decay in (Girerd 2010).
Exon 07 Splice site c.967_968insA c.967_967+1insA p.Asp323fs Pathogenic Machado (2006)
Reported once, patient had taken Fenfluramine.
Intron 7 Splice site c.967+5G>T c.967+5G>T p.? Pathogenic Girerd (2010)
Splice site defect
Intron 7 Splice site c.965-2A>C c.968-2A>C p.? Pathogenic Wang (2010)
Patient 8: inactivation of acceptor-splice site, age 30; position was reported as c.965-2A>C, no family history of PAH.
Exon 08-09 Deletion 968-?_1276+?del ex08-09del p.? Pathogenic Aldred (2006)
ID:5527, predicted consequence: in-frame deletion of 103 amino acids, kinase domain.
Exon 08 Deletion del ex8 ex08del p.? Pathogenic Girerd (2010)  
Exon 08 Frameshift c.968_969insT c.969dup p.His324fs Pathogenic Elliott (2006)
Pt 3: age 46.
Exon 08 Frameshift c.980delC c.980del p.Pro327fs Pathogenic Machado (2006)  
Exon 08 Nonsense c.994C>T c.994C>T p.Arg332X Pathogenic Thomson (2000)
Patient 5: paternal inheritance, not found in 150 normal control chromosomes in (Thomson 2000). Family US50: two affected family members, age at disease onset ranged from 28-32; Family US13: eight affected family members and two obligate carriers, age at disease onset ranged from 13-42, obligate carriers ages were 45 and 71 (Machado 2001). Family 6: variant affects the kinase domain in (Sankelo 2005). Reported once in (Wong 2005). Reported twice in (Machado 2006). Patient 114: age 30; Patient 116: age 54 (Elliott 2006). Reported as a mutational hotspot in the kinase domain in (Wang 2010). Patient 16: age 30, family history of PAH (Rosenzweig 2008). Reported once in (Portillo 2009). Also reported in (Girerd 2010).
Exon 08 Nonsense c.1001T>G c.1001T>G p.Leu334X Pathogenic Machado (2006)
Reported once in (Machado 2006) , (Girerd 2010) and (Sztrymf 2008).
Exon 08 Missense c.1019T>C c.1019T>C p.Leu340Pro Pathogenic Sztrymf (2008)
Patient 33 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 08 Missense c.1039T>C c.1039T>C p.Cys347Arg Suspected Pathogenic Machado (2006)  
Exon 08 Missense c.1040G>A c.1040G>A p.Cys347Tyr Suspected Pathogenic Machado (2006)  
Exon 08 Missense c.1042G>A c.1042G>A p.Val348Ile Pathogenic Lane (2000)
Family UK06: not found in 214 chromosomes from healthy controls, amino acid located in the kinase domain; protein change was reported as C347Y in (Lane 2000). Patient 9: age 24, family history of PAH (Wang 2010).
Exon 08 Missense c.1066A>T c.1066A>T p.Met356Leu Suspected Pathogenic Wang (2010)
Patient 10: age 26, no family history of PAH.
Exon 08 Frameshift 1076delC c.1076del p.Thr359fs Pathogenic Machado (2001)
Family US94: two affected family members, age at disease onset ranged from 39-42.
Exon 08 Frameshift c.1099-1103delGGGGA c.1099_1103del p.Glu368fs Pathogenic Deng (2000)
Family PPH010: kinase domain, not found in 196 chromosomes (Deng 2000). Reported once in (Machado 2006). Patient 34 in (Sztrymf 2008). Reported once, predicted to escape nonsense mediated decay in (Girerd 2010).
Exon 08 Synonymous 1107A>G c.1107A>G p.= Benign Machado (2001)
Found in individuals not at risk for the disease (Machado 2001). Polymorphism with a frequency of 1.1% (Machado 2006).
Exon 08 Frameshift c.1113_1114insT c.1113dup p.Ala372fs Pathogenic Elliott (2006)
Pt 48: age 21.
Exon 08 Frameshift c.1113delT c.1113del p.Asn371fs Pathogenic Machado (2006)  
Exon 08 Nonsense c.1120delA c.1120del p.Ile374X Pathogenic Machado (2006)
Reported once, patient was reported to have pulmonary veno-occlusive disease.
Intron 08 Splice site c.1128+1G>A c.1128+1G>A p.? Pathogenic Machado (2006)  
Intron 08 Splice site c.IVS8+1G>T c.1128+1G>T p.? (p.Asp323_Pro425del) Pathogenic Rindermann (2003)
Family 3771: this substitution is located in the donor splice-site of intron 8 (Rindermann 2003). Patient K3771A: reported once in (Koehler 2004). Family 67: Sequencing analysis of genomic DNA; RT-PCR studies showed deletion of exons 8-9, MLPA analysis was negative for an Exon 08-9 deletion, alteration of this nucleotide inactivated the donor splice-site resulting in an inflame deletion of codons 323-425, transcript was no subject to nonsense mediated decay (Cogan 2006).
Intron 08 Splice site c.1129-3C>G c.1129-3C>G p.? (p.Val377fs) Pathogenic Machado (2001)
Family US80: six affected family members, age at disease onset ranged from 24-53, inactivates Exon 09 acceptor site (Machado 2001). Reported once in (Machado 2006). Family 59: Sequencing analysis of genomic DNA; RT-PCR studies showed a deletion of Exon 09, MLPA analysis was negative for an Exon 09 deletion, acceptor site id disrupted resulting in a deletion of Exon 09 and a frameshift at codon 377 with the generation of PTC 47 codons downstream; transcript was subject to nonsense mediated decay (Cogan 2006). Pt 146: age 43 in (Elliott 2008).
Exon 09 Nonsense c.1146T>G c.1146T>G p.Tyr382X Pathogenic Rosenzweig (2008)
Patient 22: age 50, no family history of PAH.
Exon 09 Missense c.1156G>A c.1156G>A p.Glu386Lys Suspected Pathogenic Rosenzweig (2008)
Patient 8: age12, no family history of PAH; authors reported p.Glu386Gln.
Exon 09 Missense c.1157A>T c.1157A>T p.Glu386Val Pathogenic Fu (2008)
Not found in 200 healthy controls, age:14, mutation tracked with the disease and the patient's mother was diagnosed at 32 in (Fu 2008). Age 14, family history of PAH in (Wang 2010).
Exon 09 Missense c.1157A>G c.1157A>G p.Glu386Gly Uncertain Koehler (2004)
Patient MHH07: reported once, unclassified variant due to lack of functional data; located in the kinase domain.
Exon 09 Missense c.1171G>A c.1171G>A p.Ala391Thr Pathogenic Sztrymf (2008)
Patient 35 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 09 Missense c.1175T>C c.1175T>C p.Val392Ala Suspected Pathogenic Wang (2010)
Patient 11: age 31, no family history of PAH.
Exon 09 Nonsense c.1191/1192delTG c.1191_1192del p.Cys397X Pathogenic Machado (2001)
Family US89: two affected family members both 26 years old at disease onset.
Exon 09 Nonsense c.1196C>G c.1196C>G p.Ser399X Pathogenic Machado (2006)  
Exon 09 Missense c.1202T>C c.1202T>C p.Leu401Ser Suspected Pathogenic Machado (2006)  
Exon 09 Nonsense c.1207C>T c.1207C>T p.Gln403X Pathogenic Uehara (2002)
Patients ages 4 and 38 at time of disease onset; not found in unaffected family members (Uehara 2002). Case 7: patient's age was 40 at the time of the study in (Morisaki 2004). Proband 19: diagnosis at age 4 with mild dyspnea and positive family history and mutation tracked with disease, father diagnosed at age 34 and sister diagnosed at age 4 (Fujiwara 2008).
Exon 09 Nonsense c.1241G>A c.1241G>A p.Trp414X Pathogenic Machado (2006)  
Exon 09 Nonsense c.1243G>T c.1243G>T p.Gly415X Pathogenic Wang (2010)
Patient 12: age 32, no family history of PAH.
Exon 09 Frameshift c.1246_1247dupGA c.1245_1246dup p.Ile416fs Pathogenic Machado (2006)
Found in a patient who also had the mutation c.1250_1253del. p.Phe417X.
Exon 09 Frameshift c.1246dupG c.1245dup p.Ile416fs Pathogenic Machado (2006)  
Exon 09 Frameshift c.1247/8insGA c.1247_1248insGA p.Ile416fs Pathogenic Thomson (2000)
Patient 7: not found in 150 normal control chromosomes.
Exon 09 Frameshift c.1248delA c.1248del p.Phe417fs Pathogenic Thomson (2000)
Patient 6: de novo, not found in 150 normal control chromosomes (Thomson 2000). Reported once in (Machado 2006). Pt 5: age 23 in (Elliott 2006).
Exon 09 Nonsense c.1250_1253delTTAT c.1250_1253del p.Phe417X Pathogenic Machado (2006)
Found in a patient who also had the mutation c.1245_1246dup. p.Ile416fs.
Exon 09 Missense c.1257A>T c.1257A>T p.Arg419Ser Suspected Pathogenic Machado (2006)  
Exon 09 Missense c.1258T>C c.1258T>C p.Cys420Arg Pathogenic Machado (2001)
Family GER01: four affected family members, age at disease onset ranged from 9-40.
Exon 09 Missense c.1259G>A c.1259G>A p.Cys420Tyr Pathogenic Morisaki (2004)
Case 8: patient's age was 27 at the time of the study in (Morisaki 2004). Reported twice in (Machado 2006).
Exon 09 Frameshift c.1272insC c.1274dup p.Gly426fs Pathogenic Machado (2006)
Reported once in (Machado 2006). Patient 36 in (Sztrymf 2008). Also reported in (Girerd 2010).
Exon 09 Splice site c.1276+1G>A c.1276+1G>A p.? Pathogenic Rosenzweig (2008)
Patient 17: age 30, family history of PAH in (Rosenzweig 2008).
Intron 9 Splice site c.1276+3A>T c.1276+3A>T p.? Pathogenic Girerd (2010)
Splice defect
Intron 9 Splice site c.1276+3A>G c.1276+3A>G p.? Uncertain Machado (2006)  
Intron 9 Intronic c.1276+4A>G c.1276+4A>G p.? Uncertain Machado (2006)  
Intron 9 Splice site c.1277-9A>G c.1277-9A>G p.? Pathogenic Sztrymf (2008)
Patient 63: splice defect, authors state that cDNA studies were done (Sztrymf 2008). Reported twice, splice defect, in (Girerd 2010). Reported as polymorphism with a frequency of 0.6% in (Machado 2006). Splice prediction suggests that this is pathogenic.
Exon 10 Deletion c.1277-?_1413+?del ex10del p.? Pathogenic Cogan (2005)
Pt 5: RT-PCR studies showed a tandem duplication of Exon 10, this causes a frame shift that leads to a premature stop codon in Exon 11 nucleotides 5-8; 34 years old at time of diagnosis (Cogan 2005). MLPA analysis (Family 5) showed duplication of Exon 10, mutant transcripts were not detected in RNA and were predicted to be subject to nonsense mediated decay (Cogan 2006). Predicted consequence, deletion of 45 amino acids, kinase domain; premature truncation in Exon 11. ID:5927, inherited from unaffected father and found in affected sister. ID: 21676; pediatric, inherited from an unaffected mother (Aldred 2006). Patient 65 and 66 in (Sztrymf 2008). Reported 7 times in (Girerd 2010).
Exon 10 Frameshift c.1279del p.Glu427fs Pathogenic Smith (unpublished)
Found in a patient with no family history of PAH, internal case.
Exon 10 Nonsense c.1297C>T c.1297C>T p.Gln433X Pathogenic Rigelsky (2008)
Family CCG00386: PAH with suspected hereditary hemorrhagic telangiectasia with lung arteriovenous malformations (Rigelsky 2008).
Exon 10 Frameshift c.1313-1316delCAGA c.1313_1316del p.Thr438fs Pathogenic Koehler (2004)
Patient K4690A.
Exon 10 Missense c.1346T>G c.1346T>G p.Met449Arg Pathogenic Cogan (2006)
Family 61: this methionine is located within the kinase domain and is highly conserved.
Exon 10 Nonsense c.1348C>T c.1348C>T p.Gln450X Pathogenic Koehler (2004)
Patient MHH09 in (Koehler 2004). Also reported in (Girerd 2010).
Exon 10 Frameshift c.1366delinsCA c.1366delinsCA p.Glu456fs Pathogenic Girerd (2010)
Predicted to escape nonsense mediated decay.
Exon 10 Frameshift c.1375_1376delAG c.1375_1376del p.Arg459fs Pathogenic Morisaki (2004)
Case 9: patient was 32 at time of study.
Exon 10 Frameshift c.1376_1377delGA c.1376_1377del p.Arg459fs Suspected Pathogenic Sankelo (2005)
Classified as suspected pathogenic because a study by Sankelo et al. did not list any evidence supporting a classification as benign and several frameshift mutations are classified as pathogenic in this codon as well as after. Family 12: de novo, variant affects the kinase domain; by studying both parents of two affected sibpairs authors stated that they were able to indirectly show that this variant was not the cause of their disease.
Exon 10 Frameshift c.1388-1389insA c.1389dup p.Glu464fs Pathogenic Koehler (2004)
Patient MHH52: reported once; authors called this as an unclassified variant due to the lack of functional studies. However, it is likely to be pathogenic.
Exon 10 Frameshift c.1392delA c.1392del p.Ala465fs Pathogenic Sztrymf (2008)
Patient 37 in (Sztrymf 2008). Reported twice in (Girerd 2010).
Exon 10 Nonsense c.1397G>A c.1397G>A p.Trp466X Pathogenic Koehler (2004)
Patient K5943A in (Koehler 2004). Pt 52: age 43 in (Elliott 2006). Reported once in (Machado 2006).
Exon 10 Frameshift c.1399delA c.1401del p.Glu468fs Pathogenic Machado (2006)
Patient 38 in (Sztrymf 2008). Reported once in (Girerd 2010) and (Machado 2006).
Intron 10 Splice site c.1413+1G>A c.1413+1G>A p.? Pathogenic Girerd (2010)
Splice defect
Intron 10 Intronic c.IVS10+3A>T c.1413+3A>T p.? Pathogenic Koehler (2004)
Patient MHH10: variant causes deletion of Exon 10.
Intron 10 Intronic c.1414-37delT c.1414-37del p.? Benign Machado (2006)
Polymorphism with a frequency of 2.7%.
Intron 10 Splice site c.1414-2A>T c.1414-2A>T p.? Pathogenic Machado (2006)
Splice defect
Exon 11-13 Deletion c.1414-?-c.3117+?del ex11-13del p.? Pathogenic Aldred (2006)
ID: 6213; Deletion of 568 amino acids, kinase and cytoplasmic domains; altered termination codon and poly-A sites; inherited from unaffected mother. Patient 67 in (Sztrymf 2008). Reported 3 times in (Girerd 2010).
Exon 11-12 Deletion c.1414-?_2866+?del ex11-12del p.? Pathogenic Machado (2001)
ID: 5181, deletion of 484 amino acids, kinase and cytoplasmic domains; premature truncation in Exon 013, found in unaffected mother. Partial deletion of 3' portion of the gene including Exon 12 with the patients age of 22, further classified in (Machado 2006). Also reported in (Girerd 2010).
Exon 11 Nonsense c.1424C>A c.1424C>A p.Ser475X Pathogenic Machado (2006)
Reported once in (Machado 2006). Also reported in (Girerd 2010).
Exon 11 Frameshift c.1426delT c.1427del p.Leu476fs Pathogenic Machado (2006)  
Exon 11 Missense c.1447T>C c.1447T>C p.Cys483Arg Pathogenic Thomson (2000)
Patient 8: not found in 150 normal control chromosomes (Thomson 2000). Patient had taken fenfluramine for 1 month, not found in 130 healthy controls (Humbert 2002). Patient 39 in (Sztrymf 2008). Reported once in (Girerd 2010).
Exon 11 Missense c.1454A>G c.1454A>G p.Asp485Gly Pathogenic Lane (2000)
Family NL01: not found in 214 chromosomes from healthy controls, amino acid located in the kinase domain.
Exon 11 Missense c.1469C>T c.1469C>T p.Ala490Val Pathogenic Machado (2006)
Reported once in (Machado 2006). Pt 45: age 42 in (Elliott 2006).
Exon 11 Missense c.1471C>T c.1471C>T p.Arg491Trp Pathogenic Deng (2000)
Family PPH001, PPH008 & PPH021: kinase domain, not found in 196 control chromosomes (Deng 2000). Patient 8: 52 years old at time of study in (Morrell 2001). Variant was found in 3 affected family members and not in 11 others analyzed, ages 14, 29, and 37, not found in 240 health control chromosomes (Zhicheng 2004). Reported in 3 patients in the same family, disease onset at ages 35, 23, and 13, cDNA numbering was reported as c.491C>T in (Jing 2004). Patient K6361A in (Koehler 2004). Reported 3 times in (Machado 2006). Mutational hotspot in the kinase domain (Wong 2005). Patients 40, 41, 42, 43, and 44 in (Sztrymf 2008). Patients 5 and 6: ages 9 and 11; both had a family history of PAH in (Rosenzweig 2008). Patient 13: ages 20, no family history of PAH; also found in another patient age 37, with a family history of PAH in (Wang 2010). Reported 9 times in (Girerd 2010). Found in a patient with a family history of PAH, internal case (Smith, unpublished).
Exon 11 Missense c.1472G>A c.1472G>A p.Arg491Gln Suspected Pathogenic Deng (2000)
Family PPH019: Not found in either parent, kinase domain, not found in 196 control chromosomes (Deng 2000). Reported twice in (Machado 2006). Family 4: variant affects the kinase domain (Sankelo 2005). Mutational hotspot in the C-terminal domain (Wong 2005). Patient 18: age 28, family history of PAH in (Rosenzweig 2008). Patients 45, 46, and 47 in (Sztrymf 2008). Reported once in (Portillo 2009). Reported 3 times in (Girerd 2010).
Exon 11 Missense c.1481C>T p.Ala494Val Uncertain dbSNP
rs2229778
Exon 11 Nonsense c.1483C>T c.1483C>T p.Gln495X Pathogenic Koehler (2004)
Patient K5590A.
Exon 11 Missense c.1487G>A c.1487G>A p.Cys496Tyr Suspected Pathogenic Machado (2006)  
Exon 11 Missense c.1509A>C c.1509A>C p.Glu503Asp Suspected Pathogenic Roberts (2004)
Child 5: PAH diagnosis at 2 years and was reported to have congenital heart defect: atrial septal defect, patent ductus arteriosus and partial anomalous pulmonary venous return; this variant was not found in 196 healthy controls or 1,000 other PAH cases.
Exon 11 Missense not given c.1535A>C p.Lys512Thr Pathogenic Machado (2001)
Family GRE01: two affected family members, age at disease onset ranged from 19-50 (Machado 2001). Case 5559: found in a patient who also had R491Q, not found in 150 healthy controls (Machado 2005).
Exon 11 Synonymous c.1545C>T c.1545C>T p.= Benign Machado (2006)
Polymorphism with a frequency of 0.25%.
Exon 11 Frameshift c.1585delC c.1585del p.Arg529fs Pathogenic Machado (2006)  
Exon 12 Deletion c.del3' ex12del p.? Pathogenic Machado (2001)
Family UKSp16: Exon 01 and 12 analyzed for dosage, undetermined 3' deletion including Exon 12, one affected family member with an age of 22 at disease onset; family history of HHT.
Exon 12 Deletion c.del3' ex12del p.? Pathogenic Trembath (2001)
Family V-1 and V-2: partial deletion of 3' of gene including Exon 12; family history of HHT.
Exon 12 Missense c.1687G>A c.1687G>A p.Val563Met Suspected Pathogenic Machado (2006)  
Exon 12 Nonsense c.1750C>T c.1750C>T p.Arg584X Pathogenic Machado (2001)
Family SWE01: two affected family members both 34 years old at disease onset (Machado 2001). Patient MHH18 in (Koehler 2004).
Exon 12 Missense c.1766A>G p.Tyr589Cys Pathogenic Moller (2010)
Reported in 2 out of 14 patients, one with a closed atrial septal defect age 49 and one with a closed ventricular septal defect age 15.
Exon 12 Nonsense c.1771C>T c.1771C>T p.Arg591X Pathogenic Sztrymf (2008)
Patient 48 in (Sztrymf 2008). Also reported once in (Girerd 2010).
Exon 12 Nonsense c.1789C>T p.Arg597X Pathogenic Smith (unpublished)
Found in a patient with no family history of PAH, internal case.
Exon 12 Missense c.1937C>G c.1937C>G p.Ala646Gly Benign Morisaki (2004)
Polymorphism found in the general population with an allele frequency of 0.5% (Morisaki 2004). Polymorphism with a frequency of 0.5% (Machado 2006).
Exon 12 Frameshift c.1954_1955dup c.1954_1955dup p.Val654fs Pathogenic Sugiyama (2004)
PAH diagnosis at 19 years (Sugiyama 2004). Case 10: patient was 22 at time of study, variant was not found in unaffected father, protein change was reported as Thr652fs (Morisaki 2004).
Exon 12 Frameshift c.1969insA c.1968dup p.Gln657fs Pathogenic Thomson (2000)
Patient 9: not found in 150 normal control chromosomes.
Exon 12 Missense c.2032A>G p.Lys678Glu Uncertain dbSNP
rs111508874
Exon 12 Missense c.2084G>T p.Gly659Val Uncertain dbSNP
rs75854140
Exon 12 Nonsense c.2124C>G c.2124C>G p.Tyr708X Pathogenic Morisaki (2004)
Case 11: patient was 38 at time of study.
Exon 12 Frameshift c.2292dupA c.2291dup p.Asn764fs Pathogenic Machado (2001)
Family UK22: three affected family member, age at disease onset ranged from 30-57.
Exon 12 Frameshift c.2305delC c.2308del p.Arg770fs Pathogenic Rosenzweig (2008)
Patient 23: age 22, no family history of PAH.
Exon 12 Synonymous c.2322G>A c.2322G>A p.= Benign Elliott (2006)
Found in 5 unrelated patients, genotype frequency (A/G) 5% in a healthy population.
Exon 12 Missense c.2324G>A c.2324G>A p.Ser775Asn Benign Machado (2006)
Polymorphism with a frequency of 5% (Machado 2006). Pt 15: age 58; Pt 23: age 33; Pt 35: age 47; Pt 96: age 26; Pt 151: age 151, no known relationship between patients (Elliott 2006). Found in 3 affected individuals, variant was called a polymorphism and was excluded from the study (Rosenzweig 2008). Frequency of 13% in chronic thromboembolic pulmonary hypertension as well and in 4% of controls (Ulrich 2009). Reported in 3 healthy controls, 2 with closed atrial septal defect and 1 with an untreated ventricular septal defect (Moller 2010). Found in 2/90 patient samples, 232%; one patient also had the pathogenic c.2617C>T, p.Arg873X variant (Smith unpublished). rs2228545
Exon 12 Synonymous c.2379A>C c.2379A>C p.= Benign Morisaki (2004)
Polymorphism found in the general population with an allele frequency of 2.1% (Morisaki 2004 & Machado 2006). Classified as a polymorphism with a frequency 1/76 in a Chinese population (Wang 2010). rs3731697.
Exon 12 Frameshift c.2386delG c.2386del p.Ala796fs Pathogenic Thomson (2000)
Patient 10, 11, and 12: de novo in patient 10, not found in 150 normal control chromosomes.
Exon 12 Frameshift c.2408insTG c.2408_2409insTG p.Val804fs Pathogenic Machado (2001)
Family US79: two affected family members, age at disease onset ranged from 51-52.
Exon 12 Frameshift c.2410_2413delGTCA c.2410_2413del p.Val804fs Pathogenic Rosenzweig (2008)
Patient 7: age 11, family history of PAH.
Exon 12 Missense c.2482G>A c.2482G>A p.Gly828Arg Uncertain dbSNP
rs1048127
Exon 12 Frameshift c.2504delC c.2504del p.Thr835fs Suspected Pathogenic Cogan (2006)
Pt 88: transcript was subject to nonsense mediated decay.
Exon 12 Missense c.2506_2522del17 c.2506_2522del p.Thr836X Pathogenic Machado (2006)  
Exon 12 Frameshift c.2521_2522dupCA c.2521_2522dup p.Arg842fs Pathogenic Sztrymf (2008)
Patient 49 in (Sztrymf 2008). Reported once in (Girerd 2010).
Exon 12 Duplication c.2521_2522dupCA c.2521_2522dup p.Arg842fs Pathogenic Sztrymf (2008)
Patient 49 in (Sztrymf 2008). Reported once in (Girerd 2010).
Exon 12 Frameshift c.2527delG c.2527del p.Ala843fs Pathogenic Machado (2006)
Reported once in (Machado 2006). Pt 6: age 29 in (Elliott 2008).
Exon 12 Missense c.2531A>G c.2531A>G p.Gln844Arg Suspected Benign Morisaki (2004)
Polymorphism found in the general population with an allele frequency of 0.5% (Morisaki 2004 and Machado 2006).
Exon 12 Frameshift c.2579delT c.2580del p.Asn861fs Pathogenic Lane (2000)
Family US55: not found in 214 chromosomes from healthy controls, this variant is likely to impede heteromeric receptor complex formation at the cell surface (Lane 2000). Family PPH015: (Deng 2000). Family UK11: three affected family members, age at disease onset ranged from 2-22 (Machado 2001). Pt 13: age 27, not found in 196 chromosomes in (Elliott 2006). Patient 19: age 28, family history of PAH in (Rosenzweig 2008).
Exon 12 Missense c.2588G>A c.2588G>A p.Ser863Asn Suspected Pathogenic Wang (2009)
Age 34, patient had a family history of PAH (Wang 2009 and 2010).
Exon 12 Nonsense c.2617C>T c.2617C>T p.Arg873X Pathogenic Deng (2000)
Family PPH018: not found in 196 chromosomes (Deng 2000). Pt 85: age 85; Pt 102: age 55, no known relationship between patients (Elliott 2006). Reported 3 times in (Machado 2006). Patient 20: age 56 in (Rosenzweig 2008). Patient 20: age 56, family history of PAH in (Rosenzweig 2008). Patients 50, 51, 52, 53, 54, and 55 in (Sztrymf 2008). Reported 6 times in (Girerd 2010). Found in a patient with no family history of PAH who also had the variant; internal case (Smith unpublished). rs137852748
Exon 12 Missense c.2618G>A c.2618G>A p.Arg873Gln Pathogenic Sztrymf (2008)
Patient 56 in (Sztrymf 2008). Reported twice in (Girerd 2010).
Exon 12 Nonsense c.2620G>T c.2620G>T p.Glu874X Pathogenic Morisaki (2004)
Case 12: patient was 14 at time of study, variant was de novo.
Exon 12 Missense c.2656C>T c.2656C>T p.Arg886Cys Suspected Benign dbSNP
rs148770894; reported in 0.1% of population
Exon 12 Missense c.2657G>A c.2657G>A p.Arg886His Benign Machado (2006)
Polymorphism with a frequency of 0.6%. rs147960425.
Exon 12 Nonsense c.2695C>T c.2695C>T p.Arg899X Pathogenic Lane (2000)
Family US33: not found in 214 chromosomes from healthy controls, this variant is likely to impede heteromeric receptor complex formation at the cell surface (Lane 2000). Patient 13: not found in 150 normal control chromosomes in (Thomson 2000). Family US91: two affected family members, age at disease onset ranged from 27-32 (Machado 2001). Case 13 and 14: found in two unrelated individuals, patients were 38 and 47 at time of study in (Morisaki 2004). Reported 3 times in (Machado 2006). Mutational hotspot in the C-terminal domain (Wong 2005). Patient 14: age 18, no family history of PAH (Wang 2010). Reported once in (Girerd 2010). rs137852741.
Exon 12 Missense c.2696G>C c.2696G>C p.Arg899Pro Pathogenic Machado (2003)
Family 11: variant affects the C-terminal cytoplasmic domain, observed to locate correctly at the cell surface and SMAD mediated intracellular signaling was not impaired; this substitution led to constitutive activation of the SMAD independent P38MAPK pathway (Sankelo 2005). rs137852752.
Exon 12 Frameshift c.2705delC c.2706del p.Asn903fs Suspected Pathogenic Abramowicz (2003)
Other findings: 27 years old, amfepramone chlorhydrate treatment for 4 and 5 weeks 3.5 and 1.5 years prior to onset; protein change was reported at position 766.
Exon 12 Missense c.2708A>G c.2708A>G p.Asn903Ser Suspected Pathogenic Machado (2006)  
Exon 12 Synonymous c.2748T>C p.= Benign dbSNP
rs16839188
Exon 12 Synonymous c.2757T>G p.= Benign dbSNP
rs28572657
Exon 12 Nonsense c.2789C>G c.2789C>G p.Ser930X Pathogenic Morisaki (2004)
Case 15 and 16: reported in two unrelated individuals, patients ages were 33 and 22 at the time of the study.
Exon 12 Missense c.2811G>C p.Arg937Ser Suspected Benign dbSNP
rs1061157
Exon 12 Synonymous c.2811G>A c.2811G>A p.= Benign Deng (2000)
Minor allele frequency of 0.21, 196 chromosomes tested (Deng 2000). Found in 7 unrelated patients (Elliott 2006). Found 15 unrelated families and in individuals not at risk for the disease (Machado 2001). Polymorphism found in the general population with an allele frequency of 2.1%, rs1061657 (Morisaki 2004 and Machado 2006). Allele frequency of 29% among patients and 15% among controls (Sankelo 2005). Classified as a polymorphism with a frequency 5/76 in a Chinese population (Wang 2010). Frequency in PAH patients was 20%, 20% in chronic thromboembolic pulmonary hypertension and in 38% of controls (Ulrich 2009). Found in 24 out of 90 patient samples, 26.6% (Smith unpublished). rs1061157
Intron 12 Intronic c.2866+39T>C p.? Benign dbSNP
rs191901528
Intron 12 Intronic c.2867-29A>T p.? Benign dbSNP
rs45528636
Exon 013 Missense c.2887G>T p.Gly963Cys Uncertain dbSNP
rs146027217. Average heterozygosity: 0.001, chromosome count: 4550.
Exon 013 Missense c.2948G>A c.2948G>A p.Arg983Gln Uncertain Morse (2002)
Patient 23: diagnosis of limited cutaneous scleroderma spectrum with positive anticentromere and rheumatoid factor autoantibodies, Ashkenazi Jewish decent, patient's age was 59. rs148099152.
Exon 013 Synonymous c.2961C>T p.= Benign dbSNP
rs144848138