ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.634C>A (p.Gln212Lys) (rs876658138)

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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 RCV000217755 SCV000272978 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000480249 SCV000570193 uncertain significance not provided 2016-05-11 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.634C>A at the cDNA level, p.Gln212Lys (Q212K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Gln212Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BMPR1A Gln212Lys occurs at a position that is conserved across species and is located in the cytoplasmic topological, IC, and GS domains (Howe 2004, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Gln212Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000217755 SCV000682905 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Invitae RCV000635471 SCV000756885 uncertain significance Juvenile polyposis syndrome 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 212 of the BMPR1A protein (p.Gln212Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 229681). 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 tolerated, 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.

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