Submissions for variant NM_000256.3(MYBPC3):c.1786G>A (p.Gly596Arg)

gnomAD frequency: 0.00007  dbSNP: rs199728019

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035433	SCV000059081	uncertain significance	not specified	2018-04-10	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000656917	SCV000208048	uncertain significance	not provided	2024-10-15	criteria provided, single submitter	clinical testing	Reported in several unrelated individuals with HCM and one adult individual with unexplained sudden death in the published literature (Chung et al. (2007) Progress In Pediatric Cardiology 23 :33-38; PMID: 21511876, 25611685, 25351510, 28166282); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies suggest p.(G596R) appears to shift the balance of MYBPC3 interaction from actin to myosin (PMID: 38042491); This variant is associated with the following publications: (PMID: 25611685, 25351510, 28166282, 28518168, 25558701, 32746448, 16267253, 27930701, 33495597, 38042491, 32841044, 35130036, 37652022, 32461654, 21511876)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083913	SCV000259413	likely benign	Hypertrophic cardiomyopathy	2025-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000250820	SCV000320153	likely benign	Cardiovascular phenotype	2024-05-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000777875	SCV000913882	uncertain significance	Cardiomyopathy	2022-12-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701), dilated cardiomyopathy (PMID: 32746448), or sudden death (PMID: 27930701). This variant has been identified in 21/203560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina	RCV001108397	SCV001265626	benign	Left ventricular noncompaction 10	2019-04-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV001108398	SCV001265627	uncertain significance	Hypertrophic cardiomyopathy 4	2019-04-19	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000777875	SCV001333606	uncertain significance	Cardiomyopathy	2018-05-30	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656917	SCV001713565	uncertain significance	not provided	2020-12-29	criteria provided, single submitter	clinical testing
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	RCV001108397	SCV002758774	uncertain significance	Left ventricular noncompaction 10	2022-12-07	criteria provided, single submitter	clinical testing	The c.1786G>A (p.Gly596Arg) MYBPC3 variant has been reported in our laboratory in a 59-year-old female patient with a clinical diagnosis of non-compaction dilated cardiomyopathy, with severe left ventricular dysfunction and with defibrillator. A nephew who died of sudden death at 45 years of age. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701). This variant is present in population databases (gnomAD allele frequency 0.0001032). ClinVar contains an entry for this variant (Variation ID: 42566). In silico analysis (CADD, PolyPhen-2, MutationTaster, SIFT y Provean) supports that this missense variant has a deleterious effect on protein structure/function, but this prediction has not been confirmed by functional studies. In summary, the available evidence for c.1054A>G (p.Arg352Gly) TP63 variant is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV001083913	SCV004842443	uncertain significance	Hypertrophic cardiomyopathy	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 596 of the MYBPC3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 21511876, 25351510, 25558701), dilated cardiomyopathy (PMID: 32746448), or sudden death (PMID: 27930701). This variant has also been identified in 21/203560 chromosomes (14/9070 Ashkenazi Jewish chromosomes) in the general population by the Genome Aggregation Database (gnomAD). Although the elevated allele frequency in the general population suggests that this variant may not be disease-causing, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Blueprint Genetics	RCV000157307	SCV000207042	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2014-10-31	no assertion criteria provided	clinical testing
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000035433	SCV000280222	uncertain significance	not specified	2013-01-21	no assertion criteria provided	clinical testing	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease