ClinVar

Description

This variant deletes 1 nucleotide in exon 5 of the TNNI3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. An experimental functional study using heart tissue from a homozygous individual affected with dilated cardiomyopathy has shown that TNNI3 protein was not expressed in heart tissue (PMID: 31568572). This variant has been reported in homozygosity in multiple individuals affected with early-onset dilated cardiomyopathy (PMID: 31568572, 35050212, 36981019); heterozygous carrier parents were either not clinically affected or were not fully clinically evaluated for TNNI3-related disorders. This variant has also been reported in heterozygosity in an individual affected with dilated cardiomyopathy (PMID: 36129056), in unclear zygosity in another individual affected with dilated cardiomyopathy (PMID: 34286374), and in an individual affected with cardiomyopathy or arrhythmia (PMID: 26688388). This variant has been identified in 9/236002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function TNNI3 truncation variants in autosomal dominant cardiovascular disorders is not clearly established. 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.