ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.2552C>T (p.Ala851Val) (rs774172488)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000201874 SCV000256662 uncertain significance Familial hypertrophic cardiomyopathy 1 2015-06-30 criteria provided, single submitter research The MYBPC3 Ala851Val is a rare variant with an allele frequency of 0.00006771 in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). We have identified this variant in 1 HCM individual, diagnosed at 28 years, with unexplained syncope and severe septal hypertrophy (LVWT = 39mm). This variant has not been previously reported in the literature or observed in other HCM cases other than described in our proband (Ingles J. et al., 2005). An additional variant MYBPC3 Glu542Gln was also identified in our proband which is known to cause HCM when present in isolation. Familial segregation did not identify the MYBPC3 Ala851Val variant in his affected son who shares a similar phenotype (MYBPC3 Glu542Gln was present). We cannot however, exclude that MYBPC3 Ala851Val alone does not cause HCM or that it is a possible modifier of disease. Therefore, we classify MYBPC3 Ala851Val as a variant of "uncertain significance".
Invitae RCV000470691 SCV000546440 uncertain significance Hypertrophic cardiomyopathy 2017-06-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 851 of the MYBPC3 protein (p.Ala851Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs774172488, ExAC 0.01%) but has not been reported in the literature in individuals with a MYBPC3-related disease. ClinVar contains an entry for this variant (Variation ID: 217837). This variant occurs with a pathogenic variant in MYBPC3 in one individual with hypertrophic cardiomyopathy (PMID:16199542). While it is unknown if these variants are on the same or opposite chromosomes, this observation could suggest that the p.Ala851Val variant is not a primary cause of disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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