ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3791G>T (p.Cys1264Phe)

dbSNP: rs397514751
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158267 SCV000208202 likely pathogenic not provided 2014-03-30 criteria provided, single submitter clinical testing p.Cys1264Phe (TGT>TTT): c.3791 G>T in exon 33 of the MYBPC3 gene (NM_000256.3). A published missense variant that is likely pathogenic was identified in the MYBPC3 gene. The C1264F variant in the MYBPC3 gene has been reported previously in association with familial dilated cardiomyopathy (DCM) (Hershberger R et al, 2010). Hershberger et al. (2010) identified C1264F in two related individuals with cardiomyopathy, which was absent in 246 control samples, and classified this variant as likely disease-causing. Additionally, the C1264F variant was not observed in approximately 6,200 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, C1264F results in a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Mutations in surrounding residues (E1265V, C1266R, E1266Y) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. 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 (CirinoA et al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Invitae RCV003586142 SCV004294779 uncertain significance Hypertrophic cardiomyopathy 2023-06-25 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1264 of the MYBPC3 protein (p.Cys1264Phe). This variant is not present in population databases (gnomAD no frequency). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 64613). This missense change has been observed in individual(s) with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 20215591, 29121657, 33782553).
OMIM RCV002508763 SCV000083043 pathogenic Cardiomyopathy, dilated, 1MM 2010-04-01 no assertion criteria provided literature only

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