ClinVar Genomic variation as it relates to human health

This missense variant replaces aspartic acid with glutamic acid at codon 610 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 610 of the MYBPC3 protein (p.Asp610Glu). 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. This variant disrupts the p.Asp610 amino acid residue in MYBPC3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18533079, 25740977, 28356264; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 519159). This variant has not been reported in the literature in individuals affected with MYBPC3-related conditions. This variant is not present in population databases (gnomAD no frequency).

The p.D610E variant (also known as c.1830C>G), located in coding exon 19 of the MYBPC3 gene, results from a C to G substitution at nucleotide position 1830. The aspartic acid at codon 610 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration has been reported in a hypertrophic cardiomyopathy cohort; however, clinical details were limited (Harper AR et al. Nat Genet, 2021 02;53:135-142). Other alterations affecting this amino acid (p.D610H, c.1828G>C and p.D610N, c.1828G>A) have also been reported in association with hypertrophic cardiomyopathy, as well as described in sudden infant death syndrome (SIDS) and exome cohorts (Olivotto I et al. Mayo Clin. Proc., 2008 Jun;83:630-8; Brito D et al. Rev Port Cardiol. 2012;31(9):577-87; Brion M et al. Forensic Sci. Int., 2012 Jun;219:278-81; Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

This missense variant replaces aspartic acid with glutamic acid at codon 610 of the MYBPC3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.