ClinVar Genomic variation as it relates to human health

Variant summary: TNNT2 c.475C>T (p.Arg159X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251464 control chromosomes (gnomAD). c.475C>T has been reported in the literature in an individual affected with Left Ventricular Noncompaction (Mazzarotto_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One submitter has provided a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg159X v ariant in TNNT2 has been identified by our laboratory in 1 African American indi vidual with DCM and LVNC. This variant has been identified in 1/10404 African Am erican chromosomes and 1/66734 European chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516469). This nonsense variant leads to a premature termination codon at position 159, which is predic ted to lead to a truncated or absent protein. Truncating variants in TNNT2 have been reported to cause disease but are rare and their significance has not been well established. In summary, while there is some suspicion for a pathogenic rol e, the clinical significance of the p.Arg159X variant is uncertain.

The p.R159* variant (also known as c.475C>T), located in coding exon 10 of the TNNT2 gene, results from a C to T substitution at nucleotide position 475. This changes the amino acid from an arginine to a stop codon within coding exon 10. This variant has been detected in an individual referred for left ventricular noncompaction genetic testing; however, clinical details were limited (Mazzarotto F et al. Genet Med, 2021 May;23:856-864). This variant has also been detected in the Framingham Heart Study cohort and has been reported as an incidental finding; however, clinical details were limited (Bick AG et al. Am J Hum Genet, 2012 Sep;91:513-9; Ramensky VE et al. Front Genet, 2021 Oct;12:709419; Yang Q et al. J Am Heart Assoc, 2022 Oct;11:e025257; van der Schoot V et al. Eur J Hum Genet, 2022 Feb;30:170-177). This alteration is expected to result in protein truncation or nonsense-mediated mRNA decay. However, loss of function of TNNT2 has not been established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.