ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.3584G>T (p.Gly1195Val) (rs730880595)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158245 SCV000208180 likely pathogenic not provided 2014-05-14 criteria provided, single submitter clinical testing p.Gly1195Val (GGC>GTC): c.3584 G>T in exon 32 of the MYBPC3 gene (NM_000256.3). The G1195V variant in the MYBPC3 gene has been reported in two patients with HCM and was not reported in at least 400 control alleles (Santos D et al., 2012; Brito D et al., 2012). The G1195V variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Additionally, this substitution occurs at a position that is completely conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, missense mutations in nearby residues (L1187R, V1192D, A1194T, L1200P) have been reported in association with HCM, supporting the functional importance of this region of the protein. However, the G1195V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties.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 HCM, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (DCM) (CirinoAet al., 2011; Hershberger R et al., 2009). The variant is found in HCM panel(s).
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223819 SCV000280265 uncertain significance not specified 2014-09-24 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.Gly1195Val Based on the information reviewed below, we classify it as a variant of unknown significance (VUS). Although this is a good candidate for a pathogenic mutation, the possibility that it is a benign variant cannot be excluded at this time. This variant has been previously reported twice in association with hypertrophic cardiomyopathy, but it is not clear if this is actually 2 reports on the same Portuguese individual. No segregation analysis is available. Santos et al. (2012, BMC Med Genet) reported this as a novel variant in one 25-year-old Portuguese male diagnosed with sporadic obstructive HCM (no family history). He also carried a p.Leu44Pro variant in CSRP3. Authors apparently from the same group (Brito et al 2012) reported it as a novel variant in one Portuguese individual with HCM and a history of sudden cardiac death in a first-degree relative. No further relatives were available for study. This is a conservative amino acid change, resulting in the replacement of a nonpolar Glycine with a nonpolar Valine. Glycine at this location is completely conserved across vertebrate species sequenced. In silico analysis with PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) predicts the variant to be “Probably Damaging” with a score of 1.0. In silico analysis predicts the variant to be probably damaging to protein structure/function. Nearby variants, within 10 amino acids to either side, have also been reported in HGMD in association with hypertrophic cardiomyopathy or LVNC: Leu1187Arg, Val1192Asp, Ala1194Thr, Leu1200Pro (as of January 2014). In total the variant has not been seen in 6200 controls and individuals from publicly available population datasets. (Our patient has African-American ancestry.) Santos et al. (2012) and Brito et al. (2012) did not detect it in 100 healthy Portuguese control individuals. This variant is not present in the NHLBI Exome Sequencing Project dataset (http://evs.gs.washington.edu/EVS/), which currently includes variant calls on 4100 Caucasian and 2000 African-American individuals (as of July 22, 2014). The phenotype of those individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. No variation at this codon is present in 1000 Genomes (http://browser.1000genomes.org) or dbSNP (http://www.ncbi.nlm.nih.gov/projects/SNP).

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