Submissions for variant NM_000256.3(MYBPC3):c.1112C>G (p.Pro371Arg)

dbSNP: rs397515887

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035370	SCV000059018	uncertain significance	not specified	2016-09-01	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Pathogenic. The p.Pro371Arg variant in MYBPC3 has been reported in 7 individuals with HCM (Girolami 2010, R ubattu 2016, Coppini 2014, LMM data), 3 of whom also carried the pathogenic p.Ly s1065fs variant. It was confirmed to be in cis (on the same allele) in two of th ese individuals, and both variants segregated with disease in 3 relatives, inclu ding 1 obligate carrier. The p.Lys1065fs variant has been detected several times in isolation (Girolami 2006*, Olivotto 2011*, Witjas-Paalberends 2013, LMM data ; *note that these manuscripts contain overlapping cohorts), suggesting that the p.Pro371Arg variant arose on its background in the compound heterozygotes. It i s unclear if the remaining 4 affected individuals also carry the p.Lys1065fs var iant. The p.Pro371Arg variant was absent from large population studies. Computat ional prediction tools and conservation analysis suggest that the p.Pro371Arg va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, while there is some suspicion for a patho genic role, the clinical significance of the p.Pro371Arg variant is uncertain.
Invitae	RCV000547807	SCV000623516	uncertain significance	Hypertrophic cardiomyopathy	2019-11-02	criteria provided, single submitter	clinical testing	This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with arginine at codon 371 of the MYBPC3 protein (p.Pro371Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27600940, 20359594, 27483260). However, in at least one of these individuals pathogenic allele[s] were also identified in MYBPC3, which suggests that this c.1112C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 42505). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000624774	SCV000740357	uncertain significance	Primary familial hypertrophic cardiomyopathy	2016-07-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001582509	SCV001820190	uncertain significance	not provided	2021-08-02	criteria provided, single submitter	clinical testing	Reported in conjunction with the c.3192dupC pathogenic variant in the MYBPC3 gene in multiple individuals in association with HCM referred for genetic testing at GeneDx and in published literature (Girolami et al., 2010; Olivotto et al., 2011; Calore et al., 2015; Rubattu et al., 2016); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect This variant is associated with the following publications: (PMID: 28986452, 27600940, 28679633, 25740977, 21835320, 20359594, 27483260)