Submissions for variant NM_004329.3(BMPR1A):c.1456C>T (p.Arg486Trp)

gnomAD frequency: 0.00001  dbSNP: rs767763451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553989	SCV000632702	uncertain significance	Juvenile polyposis syndrome	2024-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 486 of the BMPR1A protein (p.Arg486Trp). This variant is present in population databases (rs767763451, gnomAD 0.006%). 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: 460487). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV000568540	SCV000668296	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-08	criteria provided, single submitter	clinical testing	The p.R486W variant (also known as c.1456C>T), located in coding exon 10 of the BMPR1A gene, results from a C to T substitution at nucleotide position 1456. The arginine at codon 486 is replaced by tryptophan, an amino acid with dissimilar 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.
Color Diagnostics, LLC DBA Color Health	RCV000568540	SCV000688243	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 486 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 hereditary cancer in the literature. This variant has been identified in 2/251492 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.
GeneDx	RCV002245000	SCV002513111	uncertain significance	not provided	2022-05-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28481359)
Baylor Genetics	RCV003476246	SCV004212628	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2024-03-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000553989	SCV004836023	uncertain significance	Juvenile polyposis syndrome	2023-04-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 486 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 hereditary cancer in the literature. This variant has been identified in 2/251492 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.