Submissions for variant NM_000256.3(MYBPC3):c.373G>T (p.Ala125Ser)

gnomAD frequency: 0.00003  dbSNP: rs370958401

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035613	SCV000059264	uncertain significance	not specified	2015-08-13	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Ala125Ser var iant in MYBPC3 has been identified by our laboratory in one individual with HCM and was present in 1/8418 European chromosomes screened by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs370958401). Alanine (A la) at position 125 is not conserved in evolution and the change to serine (Ser) was predicted to be benign using a computational tool clinically validated by o ur laboratory. This tool's benign prediction is estimated to be correct 89% of t he time (Jordan 2011). In summary, while the clinical significance of the p.Ala1 25Ser variant is uncertain, these data suggest that it is more likely to be beni gn.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035613	SCV000747957	likely benign	not specified	2025-04-08	criteria provided, single submitter	clinical testing	PM2, BP2, BP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629003	SCV000749913	uncertain significance	Hypertrophic cardiomyopathy	2024-04-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 125 of the MYBPC3 protein (p.Ala125Ser). This variant is present in population databases (rs370958401, gnomAD 0.007%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 42738). 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 serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV001547624	SCV001767376	uncertain significance	not provided	2021-03-04	criteria provided, single submitter	clinical testing	Reported in patients referred for hypertrophic cardiomyopathy (Walsh et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 42738; Landrum et al., 2016); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27532257)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486551	SCV004239386	uncertain significance	Cardiomyopathy	2022-10-05	criteria provided, single submitter	clinical testing