Submissions for variant NM_004329.3(BMPR1A):c.1376A>G (p.Asn459Ser)

dbSNP: rs1564725605

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779841	SCV000916690	uncertain significance	not specified	2017-11-02	criteria provided, single submitter	clinical testing	Variant summary: The c.1376A>G (p.Asn459Ser) in BMPR1A gene is a missense variant involves a highly conserved nucleotide and 2/4 in silico tools predict benign outcome, however no functional studies supporting these predictions were published at the time of evaluation. The variant is located within tyrosine kinase functional domain. The c.1376A>G variant is absent from the control population datasets of ExAC and gnomAD (121406 and 246258 chrs tested, respectively). To our knowledge, the variant has not been reported in affected individuals via published reports or cited by reputable databases/clinical laboratories. Taken together, the variant was classified as VUS, until new information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001303180	SCV001492419	uncertain significance	Juvenile polyposis syndrome	2024-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 459 of the BMPR1A protein (p.Asn459Ser). This variant is not present in population databases (gnomAD no frequency). 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: 632674). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BMPR1A protein function with a negative predictive value of 80%. 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	RCV004601267	SCV005095233	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-27	criteria provided, single submitter	clinical testing	The p.N459S variant (also known as c.1376A>G), located in coding exon 10 of the BMPR1A gene, results from an A to G substitution at nucleotide position 1376. The asparagine at codon 459 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV001303180	SCV005425472	uncertain significance	Juvenile polyposis syndrome	2024-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 459 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 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.