ClinVar Genomic variation as it relates to human health

The c.430C>T (p.Arg144Trp) variant identified in TNNT2 has been reported in the literature in at least two individuals affected with hypertrophic cardiomyopathy [PMID: 27532257, 33297573], and has been deposited in ClinVar as a Variant of Uncertain Significance [ClinVar ID:127070]. The c.430C>T variant is observed in 3 out of 588,858 heterozygous alleles (no homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8) which might include individuals with cardiac abnormalities. The variant is located in exon 10 of this 16-exon gene, and is predicted to replace an evolutionarily conserved arginine aminoacid with tryptophan at position 144 in the Troponin domain of the encoded protein [uniport ID: P45379]. In silico predictions are in favor of damaging effect forp.(Arg144Trp) [REVEL score = 0.796]. An in vitro functional study showed that the induced pluripotent stem cell-differentiated cardiomyocytes (iPSC-CMs) carrying thec.430C>T p.(Arg144Trp) variant had an impaired response to isoproterenol when compared to the control iPSC-CMs [PMID: 30565988]. Based on available evidence, this c.430C>T p.(Arg144Trp) variant identified in TNNT2 is classified as Likely Pathogenic.

This missense variant replaces arginine with tryptophan at codon 134 of the TNNT2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with hypertrophic cardiomyopathy (PMID: 27532257). This variant has been identified in 1/249858 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, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 134 of the TNNT2 protein (p.Arg134Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with dilated cardiomyopathy and/or hypertrophic cardiomyopathy (PMID: 27532257, 33297573; Invitae). This variant is also known as R144W. ClinVar contains an entry for this variant (Variation ID: 127070). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TNNT2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TNNT2 function (PMID: 30565988). This variant disrupts the p.Arg134 amino acid residue in TNNT2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20031601, 22464770). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Reported in association with cardiomyopathy in unrelated patients in published literature and referred for genetic testing at GeneDx (PMID: 27532257, 34853230, 33297573, 38473809); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30565988, 23861362, 33297573, 34853230, 27532257, 38473809, 37652022, 20031601)

The p.R134W variant (also known as c.400C>T), located in coding exon 9 of the TNNT2 gene, results from a C to T substitution at nucleotide position 400. The arginine at codon 134 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been detected in two individuals from hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 02;19:192-203; Micheu MM et al. Diagnostics (Basel), 2020 Dec;10). The variant (referred to as p.R144W c.430C>T) co-occurred with an MYH7 variant in an individual with findings of left ventricular non-compaction findings (Miyake W et al. Int Heart J, 2021;62:1420-1429). This alteration has also been reported as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46). 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.