Submissions for variant NM_000256.3(MYBPC3):c.2939G>A (p.Arg980His)

gnomAD frequency: 0.00004  dbSNP: rs727503179

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151081	SCV000198830	uncertain significance	not specified	2013-07-17	criteria provided, single submitter	clinical testing	The Arg980His variant in MYBPC3 has been identified in 3 unaffected individuals from 1963 individuals participating in the Jackson Heart Study (Bick 2012) and h as not been reported in individuals with cardiomyopathy. Data from large populat ion studies is insufficient to assess the frequency of this variant. Computation al analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhe n2, and SIFT) suggest that this variant may impact the protein, though this info rmation is not predictive enough to determine pathogenicity. In summary, additio nal information is needed to fully assess the clinical significance of this vari ant.
Invitae	RCV001210701	SCV001382200	uncertain significance	Hypertrophic cardiomyopathy	2022-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 980 of the MYBPC3 protein (p.Arg980His). This variant is present in population databases (rs727503179, gnomAD 0.01%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 164054). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798468	SCV002042184	uncertain significance	Cardiomyopathy	2020-06-05	criteria provided, single submitter	clinical testing
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV002254280	SCV002525525	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2022-03-17	criteria provided, single submitter	clinical testing	The c.2939G>A variant is not present in publicly available population databases like 1000 Genomes, EVS, ExAC and Indian Exome Database. Heterozygous state of the variant is present in Genome Aggregation Database (gnomAD), at a very low frequency. The variant was previously identified in patients affected with hypertrophic cardiomyopathy (PMID:27532257) and reported to HGMD (ID: CM1616999). The variant was also several times reported to ClinVar as uncertain significance, mainly due to lack of established functional studies (Accession: VCV000164054.4). The variant had also been identified in 3 unaffected individuals from 1963 individuals participating in the Jackson Heart Study (PMID:22958901) and had not been reported in individuals with cardiomyopathy. In-silico pathogenicity prediction programs like SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant to be likely deleterious, however these predictions were not confirmed by any published functional studies.
Fulgent Genetics, Fulgent Genetics	RCV002254280	SCV002776434	uncertain significance	Hypertrophic cardiomyopathy 4; Left ventricular noncompaction 10	2021-11-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001798468	SCV004358653	uncertain significance	Cardiomyopathy	2022-01-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 980 of the MYBPC3 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 been reported in an individual affected with hypertrophic cardiomyopathy (MID: 27532257). This variant has been identified in 4/202388 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.