Submissions for variant NM_000256.3(MYBPC3):c.1934C>T (p.Pro645Leu)

dbSNP: rs397515938

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035454	SCV000059102	uncertain significance	not specified	2018-01-05	criteria provided, single submitter	clinical testing	The p.Pro645Leu variant in MYBPC3 has been identified by our laboratory in 2 ind ividuals with HCM, one of whom also carried a likely pathogenic variant in MYBPC 3. It was absent from large population studies. This variant has been reported i n ClinVar (Variation ID: 42586). Computational prediction tools and conservation analysis suggest that the p.Pro645Leu variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Pro645Leu variant is uncertain.
GeneDx	RCV000158134	SCV000208069	likely pathogenic	not provided	2014-05-12	criteria provided, single submitter	clinical testing	p.Pro645Leu (CCC>CTC): c.1934 C>T in exon 21 of the MYBPC3 gene (NM_000256.3) The P645L variant that is likely pathogenic was identified in the MYBPC3 gene. It has not been published as a mutation or reported as a benign polymorphism to our knowledge. The P645L 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. The P645L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense mutations in nearby residues (R654C, R654H) have been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. 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).
Blueprint Genetics	RCV000208032	SCV000264031	likely pathogenic	Primary familial hypertrophic cardiomyopathy	2015-12-08	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000035454	SCV000748015	uncertain significance	not specified	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV001241239	SCV001414245	uncertain significance	Hypertrophic cardiomyopathy	2019-11-06	criteria provided, single submitter	clinical testing	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. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 27532257, Invitae). ClinVar contains an entry for this variant (Variation ID: 42586). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 645 of the MYBPC3 protein (p.Pro645Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.