ClinVar Miner

Submissions for variant NM_000256.3(MYBPC3):c.1783A>G (p.Ile595Val)

dbSNP: rs730880550
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158112 SCV000208047 uncertain significance not provided 2019-12-17 criteria provided, single submitter clinical testing Reported in association with HCM; however, no additional clinical information was provided (Ho et al., 2018); Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30297972, 28679633, 30847666)
Invitae RCV001857560 SCV002211614 uncertain significance Hypertrophic cardiomyopathy 2022-05-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 595 of the MYBPC3 protein (p.Ile595Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 30297972, 30847666, 33782553). ClinVar contains an entry for this variant (Variation ID: 180948). 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. 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.
Ambry Genetics RCV002399570 SCV002711271 uncertain significance Cardiovascular phenotype 2022-10-18 criteria provided, single submitter clinical testing The p.I595V variant (also known as c.1783A>G), located in coding exon 18 of the MYBPC3 gene, results from an A to G substitution at nucleotide position 1783. The isoleucine at codon 595 is replaced by valine, an amino acid with highly similar properties. This variant was detected in hypertrophic cardiomyopathy and cardiomyopathy genetic testing cohorts; however, clinical details were sometimes limited, and additional cardiac variants were detected in some cases (Ho CY et al. Circulation, 2018 10;138:1387-1398; Mazzarotto F et al. Genet Med, 2019 02;21:284-292; van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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