Submissions for variant NM_000256.3(MYBPC3):c.2914C>T (p.Arg972Trp)

gnomAD frequency: 0.00096  dbSNP: rs193922382

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035542	SCV000052954	likely benign	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2914C>T (p.Arg972Trp) results in a non-conservative amino acid change located in the Immunoglobulin-like domain (IPR007110) of the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 185800 control chromosomes, predominantly at a frequency of 0.0037 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 3.7-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.2914C>T has been reported in the literature in individuals affected with Cardiomyopathy without strong evidence of causality (Bick_2012, Burstein_2021). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22958901, 32746448). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035542	SCV000059192	benign	not specified	2022-03-23	criteria provided, single submitter	clinical testing	The p.Arg972Trp variant in MYBPC3 is classified as benign because it has been identified in 0.3% (58/18682) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). In addition, one mammalian species (elephant) carries a tryptophan at this position, despite high nearby amino acid conservation, further supporting a benign role. ACMG/AMP Criteria applied: BA1.
GeneDx	RCV001529595	SCV000207991	likely benign	not provided	2021-04-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22958901)
Ambry Genetics	RCV000245670	SCV000318294	likely benign	Cardiovascular phenotype	2018-08-02	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.
Invitae	RCV000466462	SCV000546448	likely benign	Hypertrophic cardiomyopathy	2024-01-20	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770332	SCV000901766	benign	Cardiomyopathy	2023-05-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000035542	SCV001157731	likely benign	not specified	2019-03-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000770332	SCV001353201	likely benign	Cardiomyopathy	2018-11-30	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529595	SCV001743294	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529595	SCV001919942	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529595	SCV001955628	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001529595	SCV001967173	likely benign	not provided		no assertion criteria provided	clinical testing
Cohesion Phenomics	RCV000466462	SCV003800598	benign	Hypertrophic cardiomyopathy	2022-10-10	no assertion criteria provided	clinical testing