rs397516484

Description

This TNNT2 Arg278His variant has been reported in 3 HCM probands (Pasquale F, et al., 2012; Walsh R et al., 2017). This variant is present in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). We have identified TNNT2 Arg278His in a proband with HCM, but no family history of disease or sudden cardiac death (Ingles et al., 2017). The proband also carries 2 other variants (TNNT2 c.571-7G>A & MYH7 c.1000-7C>T). Interestingly, different rare variants at this position (Arg278Cys and Arg278Pro) have also been reported in multiple HCM individuals, suggesting that an amino acid substitution at this site may not be tolerated. Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), the variant is rare in the general population (PM2), has been identified in 4 HCM probands and in silico tools predict the variant to be deleterious, therefore we classify TNNT2 Arg278His as a variant of "uncertain significance".

This missense variant replaces arginine with histidine at codon 278 of the TNNT2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in three individuals affected with hypertrophic cardiomyopathy (PMID: 22144547, 28771489, 28971120). This variant has also been identified in 4/275756 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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 arginine with histidine at codon 278 of the TNNT2 protein (p.Arg278His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs397516484, ExAC 0.02%). This missense change has been observed in individual(s) with hypertrophic cardiomyopathy (PMID: 20624503, 22144547, 27532257, 28408708, 33297573). This variant is also known as p.Arg288His. ClinVar contains an entry for this variant (Variation ID: 43674). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg278 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12974739, 15958377, 23283745, 24793961). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.