Submissions for variant NM_004329.3(BMPR1A):c.49A>C (p.Ile17Leu)

dbSNP: rs778886055

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216319	SCV000274861	benign	Hereditary cancer-predisposing syndrome	2022-09-22	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701225	SCV000830016	uncertain significance	Juvenile polyposis syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 17 of the BMPR1A protein (p.Ile17Leu). This variant is present in population databases (rs778886055, gnomAD 0.02%). 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: 231113). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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	RCV000758774	SCV000887604	uncertain significance	not provided	2018-07-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000216319	SCV000912932	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 17 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 been identified in 7/251326 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193976	SCV001363176	uncertain significance	not specified	2024-07-15	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.49A>C (p.Ile17Leu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251326 control chromosomes, predominantly in the Latino cohort with an allele frequency of 0.0002. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.49A>C in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 231113). Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV000758774	SCV001791446	uncertain significance	not provided	2019-11-04	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Sema4, Sema4	RCV000216319	SCV002528606	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Baylor Genetics	RCV003475014	SCV004210973	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2023-09-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000701225	SCV004840681	uncertain significance	Juvenile polyposis syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 17 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 been identified in 7/251326 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.
PreventionGenetics, part of Exact Sciences	RCV003982966	SCV004796762	uncertain significance	BMPR1A-related disorder	2024-02-15	no assertion criteria provided	clinical testing	The BMPR1A c.49A>C variant is predicted to result in the amino acid substitution p.Ile17Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD, indicating it is rare. This variant is interpreted by vast majority of the submitters in ClinVar as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/231113/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.