Submissions for variant NM_000256.3(MYBPC3):c.2997C>T (p.Gly999=)

gnomAD frequency: 0.00071  dbSNP: rs377283955

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035547	SCV000059197	likely benign	not specified	2015-08-21	criteria provided, single submitter	clinical testing	p.Gly999Gly in exon 29 of MYBPC3: This variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located within the splice consensus region. This variant has been identified in 0.1% (8/ 8424) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://e xac.broadinstitute.org; dbSNP rs377283955).
GeneDx	RCV000035547	SCV000170440	benign	not specified	2013-06-12	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000232545	SCV000284236	benign	Hypertrophic cardiomyopathy	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618610	SCV000736571	likely benign	Cardiovascular phenotype	2018-09-05	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770329	SCV000901763	benign	Cardiomyopathy	2017-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035547	SCV000917814	likely benign	not specified	2018-05-08	criteria provided, single submitter	clinical testing	Variant summary: MYBPC3 c.2997C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within African control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in MYBPC3 causing Hypertrophic Cardiomyopathy phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.2997C>T in individuals affected with Hypertrophic Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign (x2) and uncertain significance (x1). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000770329	SCV001342461	benign	Cardiomyopathy	2018-10-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549427	SCV004740113	likely benign	MYBPC3-related disorder	2019-09-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).