ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.356C>T (p.Thr119Ile) (rs184709702)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159216 SCV000209162 uncertain significance not provided 2012-08-21 criteria provided, single submitter clinical testing The Thr119Ile variant in the TNNI3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Thr119Ile results in a semi-conservative amino acid substitution of a neutral, polar Threonine to a non-polar Isoleucine at a position that is moderately conserved across species. In silico analysis predicts Thr119Ile is benign to the protein structure/function. However, nearby mutations (Ala116Gly, Asp127Tyr) have been reported in association with cardiomyopathy, supporting the functional significance of this region of the protein. In addition, the NHLBI ESP Exome Variant Server reports Thr119Ile was not observed in approximately 6000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.The variant is found in DCM panel(s).
Invitae RCV000231010 SCV000284656 uncertain significance Hypertrophic cardiomyopathy 2016-02-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 119 of the TNNI3 protein (p.Thr119Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TNNI3-related disease. ClinVar contains an entry for this variant (Variation ID: 181579). The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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