ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1420G>C (p.Val474Leu) (rs567733221)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129399 SCV000184166 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000467583 SCV000552894 uncertain significance Juvenile polyposis syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 474 of the BMPR1A protein (p.Val474Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs567733221, ExAC 0.01%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 141060). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 RCV000481877 SCV000571439 uncertain significance not provided 2017-06-07 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1420G>C at the cDNA level, p.Val474Leu (V474L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). This variant was observed in a cohort of individuals that underwent hereditary cancer panel testing (Yurgelun 2015). BMPR1A Val474Leu was observed at an allele frequency of 0.006% (4/66,736) in individuals of European ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. BMPR1A Val474Leu occurs at a position that is conserved across species and is located within the protein kinase domain (Howe 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Val474Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129399 SCV000688241 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-22 criteria provided, single submitter clinical testing

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