ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.340A>G (p.Ile114Val) (rs730881070)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159215 SCV000209161 uncertain significance not provided 2012-04-25 criteria provided, single submitter clinical testing The Ile114Val variant in the TNNI3 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ile114Val results in a conservative amino acid substitution of one non-polar amino acid with another at a position that is not conserved. In silico analysis predicts Ile114Val is benign to the protein structure/function. Nevertheless, a mutation in a nearby codon (Ala116Gly) has been reported in association with cardiomyopathy, supporting the functional importance of this region of the protein. Also, The NHLBI ESP Exome Variant Server reports Ile114Val was not observed in approximately 5,000 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 HCM panel(s).
Color Health, Inc RCV000778011 SCV000914121 likely benign Cardiomyopathy 2018-10-05 criteria provided, single submitter clinical testing
Invitae RCV001294731 SCV001483621 uncertain significance Hypertrophic cardiomyopathy 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 114 of the TNNI3 protein (p.Ile114Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs730881070, ExAC 0.002%). This variant has not been reported in the literature in individuals with TNNI3-related conditions. ClinVar contains an entry for this variant (Variation ID: 181578). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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