Submissions for variant NM_004329.3(BMPR1A):c.712C>G (p.Arg238Gly)

dbSNP: rs747728399

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520400	SCV000617154	uncertain significance	not provided	2017-05-03	criteria provided, single submitter	clinical testing	This variant is denoted BMPR1A c.712C>G at the cDNA level, p.Arg238Gly (R238G) at the protein level, and results in the change of an Arginine to a Glycine (CGG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BMPR1A Arg238Gly was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Arg238Gly occurs at a position that is conserved across species and is located in the Protein Kinase 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 Arg238Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000557396	SCV000632731	uncertain significance	Juvenile polyposis syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 238 of the BMPR1A protein (p.Arg238Gly). This variant is present in population databases (rs747728399, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of juvenile polyposis syndrome (PMID: 30680046). ClinVar contains an entry for this variant (Variation ID: 449255). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt BMPR1A function with a positive predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000581103	SCV000682911	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 238 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 performed for this variant. This variant has been reported in an individual affected with duodenal polyposis in the literature (PMID: 30680046). This variant has been identified in 6/282802 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000520400	SCV001133469	uncertain significance	not provided	2018-10-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000581103	SCV002531113	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	curation
Ambry Genetics	RCV000581103	SCV002665770	benign	Hereditary cancer-predisposing syndrome	2021-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
PreventionGenetics, part of Exact Sciences	RCV003424076	SCV004118197	uncertain significance	BMPR1A-related disorder	2023-05-03	criteria provided, single submitter	clinical testing	The BMPR1A c.712C>G variant is predicted to result in the amino acid substitution p.Arg238Gly. This variant has been reported in an individual with colorectal adenomas (Henn et al. 2019. PubMed ID: 30680046). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-88676927-C-G) and has conflicting interpretations of benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/449255/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV003476215	SCV004212645	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2023-06-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000557396	SCV004842883	uncertain significance	Juvenile polyposis syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 238 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 performed for this variant. This variant has been reported in an individual affected with duodenal polyposis in the literature (PMID: 30680046). This variant has been identified in 6/282802 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.