Submissions for variant NM_000364.4(TNNT2):c.347_348delinsCT (p.Ile116Thr) (rs1553282523)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520713	SCV000621578	uncertain significance	not specified	2017-10-09	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TNNT2 gene. The c.317_318delTCinsCT variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The c.317_318delTCinsCT variant causes deletion of two nucleotides and insertion of two nucleotides, resulting in the amino acid substitution of I106T with no shift in reading frame and no creation of a premature stop codon. The I106T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, and it occurs at a position that is conserved across species. Furthermore, in silico analysis predicts the I106T variant is probably damaging to the protein structure/function. Nevertheless, in the absence of functional mRNA studies, the physiological consequences of the c.317_318delTCinsCT variant cannot be precisely determined. Missense variants in nearby residues (A104V, F110I, F110L) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014), supporting the functional importance of this region of the protein.
Invitae	RCV000646067	SCV000767824	uncertain significance	Familial hypertrophic cardiomyopathy 2; Left ventricular noncompaction 6; Familial restrictive cardiomyopathy 3	2017-11-03	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 106 of the TNNT2 protein (p.Ile106Thr). The isoloeucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TNNT2-related disease. A computational algorithm designed to assess the pathogenicity of variants in TNNT2 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.