rs483352832

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg144Trp variant in TNNT2 has been reported in 1 individual with dilated cardiomyopathy and segregated with disease in 4 affected relatives, including 1 obligate carrier (Rani 2014). It has also been identified in 4/30504 South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID #132943). An in vitro functional study suggests that this variant may disrupt troponin binding (Gangadharan 2017) and computational prediction tools suggest that it may impact the protein, though this information is not predictive enough to determine pathogenicity.In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria Applied: PS3_Supporting, PP1, PP3.

This missense variant replaces arginine with tryptophan at codon 144 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). Functional studies have shown that this variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity (PMID: 28973951). However, clinical relevance of this observation is not known. This variant has been shown to segregate with dilated cardiomyopathy in an Indian family (4 affected carriers and 8 unaffected non-carriers) (PMID: 24992688). This variant has also been identified in 8/249866 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.

The heterozygous p.Arg144Trp missense variant identified in TNNT2 has been reported in a South Indian family affected with late-onset familial dilated cardiomyopathy and sudden cardiac death (SCD) [PMID: 24992688]. The variant was detected in four affected family members (one additional obligate carrierdeceasedpatientwhose DNA was not available for analysis) and was absent in eleven unaffected family members [PMID: 24992688]. ClinVar has an entry of this variant [ClinVar ID:132943]. The p.Arg144Trp variant has overall 0.00003 allele frequency in gnomAD database (8 out of 249,866 heterozygous alleles) and 0.00013 allele frequency (4 out of 30,504 heterozygous alleles) in South Asian subpopulation represented in the gnomAD database. The variant affects a moderately conserved residue, is located within functionally important tropomyosin-binding domain (residues ~80-180) and is predicted “deleterious” by multiple in silico prediction tools. In vitro functional experiments suggest that the p.Arg144Trp variant may increase the binding affinity for tropomyosin and reduce Ca2+ sensitivity [PMID: 28973951]. Based on the available evidence, the p.Arg144Trp variant in the TNNT2 gene is assessed as likely pathogenic.