ClinVar

Description

Variant classified as Uncertain Significance - Favor Pathogenic. The p.Asp180fs variant in TNNI3 has not been previously reported in individuals with cardiomyop athy or in large population studies. This frameshift variant is predicted to alt er the protein?s amino acid sequence beginning at position 180 and lead to a pre mature termination codon 19 amino acids downstream. This termination codon occur s within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. While he terozygous frameshift variants in TNNI3 are uncommon, they have been reported in cases of HCM (Olivotto 2008, Olivotto 2011) and RCM with functional evidence of calcium sensitization (Kaski 2008, Kostareva 2009). However, it remains unclear if the p.Asp180fs variant would impact protein function. In summary, while ther e is some suspicion for a pathogenic role, the clinical significance of the p.As p180fs variant is uncertain.