ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1829A>T (p.Asp610Val) (rs730880554)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158124 SCV000208059 pathogenic not provided 2014-04-01 criteria provided, single submitter clinical testing p.Asp610Val (GAC>GTC): c.1829 A>T in exon 19 of the MYBPC3 gene (NM_000256.3). While the D610V mutation in the MYBPC3 gene has not been reported to our knowledge, mutations affecting this same residue, (D610H, D610N), have been reported in association with HCM (Olivetto I et al., 2008; Brito D et al., 2012). Additionally, mutations in nearby residues (P608S, P608L, E611K, E619K) have been reported in association with cardiomyopathy, further supporting the functional importance of this residue and this region of the protein. D610V 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. In silico analysis predicts D610V is probably damaging to the protein structure/function. Furthermore, D610V 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.In summary, D610V 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, 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 RCV000233359 SCV000284216 uncertain significance Hypertrophic cardiomyopathy 2017-04-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 610 of the MYBPC3 protein (p.Asp610Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 180954). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000244432 SCV000320163 uncertain significance Cardiovascular phenotype 2015-08-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence

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