Submissions for variant NM_000256.3(MYBPC3):c.502G>A (p.Val168Met)

gnomAD frequency: 0.00002  dbSNP: rs569740494

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000168744	SCV000208222	uncertain significance	not provided	2017-04-26	criteria provided, single submitter	clinical testing	p.Val168Met (GTG>ATG): c.502 G>A in exon 4 of the MYBPC3 gene (NM_000256.3). The V168M variant in the MYBPC3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The V168M variant is a conservative amino acid substitution as these residues share similar properties, and are least likely to impact secondary structure. The V168 residue is not conserved across species. In silico analysis was inconsistent with regard to the effect this variant may have on the protein structure/function. Nevertheless, mutations in nearby residues (R160W, P161S, E165D, R177C, R177H) have been reported in association with HCM, supporting the functional importance of this region of the protein. The V168M variant was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088395	SCV001051683	likely benign	Hypertrophic cardiomyopathy	2024-10-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001182257	SCV001347647	likely benign	Cardiomyopathy	2021-01-07	criteria provided, single submitter	clinical testing
Phosphorus, Inc.	RCV001823717	SCV002073395	likely benign	not specified	2022-01-13	criteria provided, single submitter	clinical testing	This missense variant resulted in an amino acid substitution of valine with methionine at codon 168 of the MYBPC3 gene. The variant has occurred in GnomAD with a total MAF of 0.0032% and with the highest MAF of 0.2181% in the South Asian population. This position is not conserved. In silico functional algorithm predicted with Polyphen calling it possibly damaging, and SIFT deleterious, but no functional studies were performed to confirm this prediction. This variant NM_000256.3(MYBPC3):c.502G>A (p.Val168Met) is present in the ClinVar database (ID: 181040). The variant has not occurred in the literature in the association with the disease. Considering that the variant has a relatively high frequency in a subpopulation, it has been classified as Likely Benign.
Ambry Genetics	RCV002345536	SCV002646302	benign	Cardiovascular phenotype	2023-04-14	criteria provided, single submitter	clinical testing	This alteration is classified as 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.