ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1498A>G (p.Met500Val) (rs376651641)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000345991 SCV000365657 uncertain significance Juvenile Polyposis 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000462223 SCV000552879 uncertain significance Juvenile polyposis syndrome 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 500 of the BMPR1A protein (p.Met500Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs376651641, ExAC 0.009%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 301353). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000486559 SCV000564705 uncertain significance not provided 2017-07-03 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1498A>G at the cDNA level, p.Met500Val (M500V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Met500Val was observed at an allele frequency of 0.01% (6/66740) in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. BMPR1A Met500Val occurs at a position that is conserved across species and is located in the protein kinase domain and topological cytoplasmic domain (Howe 2004, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BMPR1A Met500Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561192 SCV000668289 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000561192 SCV000688248 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-08 criteria provided, single submitter clinical testing
Wendy Chung Laboratory,Columbia University Medical Center RCV000664164 SCV000784722 uncertain significance Pulmonary arterial hypertension associated with congenital heart disease 2018-06-27 criteria provided, single submitter case-control

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