Submissions for variant NM_004329.3(BMPR1A):c.1481G>A (p.Arg494Gln)

gnomAD frequency: 0.00001  dbSNP: rs1204089728

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000580696	SCV000682873	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 494 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 hereditary cancer in the literature. This variant has been identified in 3/282888 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635429	SCV000756842	uncertain significance	Juvenile polyposis syndrome	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 494 of the BMPR1A protein (p.Arg494Gln). This variant is present in population databases (no rsID available, gnomAD 0.005%). 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: 489690). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985357	SCV001133464	uncertain significance	not provided	2023-11-07	criteria provided, single submitter	clinical testing	The BMPR1A c.1481G>A (p.Arg494Gln) variant has been reported in the published literature in a healthy individual (PMID: 36243179 (2022)). To the best of our knowledge, this variant has not been reported in individuals with BMPR1A-related cancers in the literature. The frequency of this variant in the general population, 0.000011 (3/282888 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV000580696	SCV001172171	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-04	criteria provided, single submitter	clinical testing	The p.R494Q variant (also known as c.1481G>A), located in coding exon 11 of the BMPR1A gene, results from a G to A substitution at nucleotide position 1481. The arginine at codon 494 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000985357	SCV002028426	uncertain significance	not provided	2021-05-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003471924	SCV004212652	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2023-05-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000635429	SCV004838514	uncertain significance	Juvenile polyposis syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 494 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 hereditary cancer in the literature. This variant has been identified in 3/282888 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.