Submissions for variant NM_004329.3(BMPR1A):c.1459T>A (p.Trp487Arg)

dbSNP: rs112883778

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985356	SCV001133463	likely pathogenic	not provided	2018-10-25	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality (0/251492 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001369693	SCV001566140	uncertain significance	Juvenile polyposis syndrome	2022-10-12	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 801057). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 487 of the BMPR1A protein (p.Trp487Arg). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BMPR1A protein function. 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.
Ambry Genetics	RCV002391044	SCV002695916	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	clinical testing	The p.W487R variant (also known as c.1459T>A), located in coding exon 10 of the BMPR1A gene, results from a T to A substitution at nucleotide position 1459. The tryptophan at codon 487 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001369693	SCV004836025	uncertain significance	Juvenile polyposis syndrome	2024-06-10	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with arginine at codon 487 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). A functional study has shown this variant to result in a partial loss of BMPR1A protein function in a luciferase reporter gene assay (PMID: 21203531). This variant has been reported in an individual affected with colorectal cancer (PMID: 21203531). This variant has not been identified 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.