Submissions for variant NM_000256.3(MYBPC3):c.1863C>T (p.Phe621=)

gnomAD frequency: 0.00032  dbSNP: rs193922378

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035445	SCV000059093	likely benign	not specified	2017-03-03	criteria provided, single submitter	clinical testing	p.Phe621Phe in exon 19 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 sequence. It has been identified in 0.1% (7/4616) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs193922378).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227047	SCV000284217	benign	Hypertrophic cardiomyopathy	2025-01-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000245194	SCV000319024	likely benign	Cardiovascular phenotype	2016-09-10	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	RCV000769322	SCV000900700	likely benign	Cardiomyopathy	2022-12-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000769322	SCV001344873	likely benign	Cardiomyopathy	2019-01-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000227047	SCV004842425	likely benign	Hypertrophic cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035445	SCV006066209	benign	not specified	2025-04-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030281	SCV000052948	likely benign	Primary familial hypertrophic cardiomyopathy	2015-10-02	no assertion criteria provided	clinical testing	The c.1863C>T (p.Phe621Phe) synonymous variant affects a non-conserved nucleotide. The Mutation Taster predicts a disease-causing outcome while 5/5 in silico programs (via Alamut) predict no significant effect on splicing. The variant was observed in the large, broad control population, ExAC with an allele frequency of 0.023% which does not exceed the maximal expected allele frequency of a disease causing MYBPC3 alleles. The variant has not been reported in CMYO patients and in vivo/vitro studies to describe the impact of the variant on splicing or mRNA levels have not been published at the time of scoring. Multiple reputable clinical laboratories classify the variant as “Likely Benign/Benign” without providing evidence. Considering all evidence, the variant of interest is classified as Possibly Normal Variant, until additional information becomes available.
PreventionGenetics, part of Exact Sciences	RCV004737166	SCV005350199	likely benign	MYBPC3-related disorder	2024-05-01	no assertion criteria provided	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).