ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3581C>T (p.Ala1194Val) (rs730880594)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158244 SCV000208179 likely pathogenic not provided 2013-03-28 criteria provided, single submitter clinical testing p.Ala1194Val (GCG>GTG): c.3581 C>T in exon 32 of the MYBPC3 gene (NM_000256.3). The Ala1194Val mutation in the MYBPC3 gene has not been published as a disease-causing mutation, however Ala1194Val has been observed in unrelated individuals tested for HCM. Although Ala1194Val results in a conservative amino acid substitution of one non-polar amino acid for another, this substitution occurs at a position that is highly conserved across species. A mutation in this same residue (Ala1194Thr) has been reported in one individual with HCM and a cardiac wall thickness of >13 mm, while it was not identified in 200 control chromosomes (Richard P et al., 2003). Also, mutations in nearby residues (Leu1187Arg, Leu1200Pro) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. In silico analysis predicts that Ala1194Val is probably damaging to the protein structure/function. In addition, Ala1194Val was absent from the 1000 Genomes database and 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. In summary, Ala1194Val in the MYBPC3 gene is interpreted as a likely disease-causing mutation. Mutations in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy (HCM), 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 DCM panel(s).
Invitae RCV000461779 SCV000546456 uncertain significance Hypertrophic cardiomyopathy 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 1194 of the MYBPC3 protein (p.Ala1194Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs730880594, ExAC 0.07%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 181012). 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. 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223738 SCV000280264 uncertain significance not specified 2013-08-01 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. MYBPC3 p.Ala1194Val This variant is novel; it has not been reported in association with cardiomyopathy or in healthy controls. This is a conservative amino acid change with the replacement of nonpolar Alanine with a nonpolar Valine. Alanine is highly conserved at this residue and in silico analysis (PolyPhen2) predicts the amino acid change to be probably damaging to protein structure and function. Richard et al (2003) reported a variant at the same codon (p.Ala1194Thr) in an individual with severe wall thickness (>13mm) and HCM. Richard et al did not find that variant in 200 control individuals. Disease associated variants have been reported in nearby codons as well (Leu187Arg, Leu1200Pro) (Human Gene Mutation Database It is not listed in dbSNP. There is insufficient data to determine whether or not this variant causes cardiomyopathy.

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