Submissions for variant NM_000256.3(MYBPC3):c.1091C>T (p.Ala364Val)

gnomAD frequency: 0.00004  dbSNP: rs778161908

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000498116	SCV000590623	uncertain significance	not provided	2017-06-19	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the MYBPC3 gene. The A364V variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 7/7736 (0.1%) alleles from individuals of East Asian ancestry in the Exome Aggregation Consortium (ExAC) dataset, indicating it may be a rare benign variant in this population (Lek et al., 2016; Exome Variant Server). The A364V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to alanine are tolerated across species and where valine is present as the wild type in at least two species. However, in silico analysis predicts this variant is probably damaging to the protein structure/function.
Color Diagnostics, LLC DBA Color Health	RCV001191865	SCV001359782	likely benign	Cardiomyopathy	2020-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857025	SCV002208279	uncertain significance	Hypertrophic cardiomyopathy	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 364 of the MYBPC3 protein (p.Ala364Val). This variant is present in population databases (rs778161908, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 432853). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. This variant disrupts the p.Ala364 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20513729, 21239446, 21302287, 25740977). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002431449	SCV002731814	likely benign	Cardiovascular phenotype	2022-09-21	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.
Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University	RCV003319202	SCV003932365	uncertain significance	Primary dilated cardiomyopathy	2023-06-01	criteria provided, single submitter	clinical testing