Submissions for variant NM_004329.3(BMPR1A):c.587A>G (p.Asp196Gly)

gnomAD frequency: 0.00002  dbSNP: rs141608069

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002525619	SCV000552866	uncertain significance	Juvenile polyposis syndrome	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 196 of the BMPR1A protein (p.Asp196Gly). This variant is present in population databases (rs141608069, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 411627). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000766536	SCV000569785	uncertain significance	not provided	2016-12-23	criteria provided, single submitter	clinical testing	This variant is denoted BMPR1A c.587A>G at the cDNA level, p.Asp196Gly (D196G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Asp196Gly was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Asp196Gly occurs at a position that is conserved across species and is located in the intracellular (IC) domain and within the cytoplasmic topological domain (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 Asp196Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000484852	SCV000731412	uncertain significance	not specified	2017-02-26	criteria provided, single submitter	clinical testing	The p.Asp196Gly variant in BMPR1A has not been previously reported in individual s with juvenile polyposis syndrome, but has been identified in 2/66666 of Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs141608069). Computational prediction tools and conservation an alysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Asp196Gly variant is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV000777241	SCV000912936	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-12	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 196 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has been identified in 3/282766 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV000777241	SCV002651801	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.