ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.482C>T (p.Ala161Val) (rs753413305)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000535232 SCV000623785 uncertain significance Hypertrophic cardiomyopathy 2019-05-29 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 161 of the TNNI3 protein (p.Ala161Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs753413305, ExAC 0.003%) but has not been reported in the literature in individuals with a TNNI3-related disease. 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 variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV001188384 SCV001355440 uncertain significance Cardiomyopathy 2019-08-22 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786224 SCV000924962 uncertain significance not provided 2016-02-22 no assertion criteria provided provider interpretation We have seen the TNNI3 Ala161Val variant in one person with HCM. Testing was done at GeneDx. Given a lack of case data we consider this variant of unknown significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant is novel. In silico analysis with Mutation Taster predicts the variant to be a polymorphism. The alanine at codon 161 is not well conserved; it is conserved in primates, but is not conserved or does not have a homologue in several other species. There are 2 of 60,108 individuals with variation at codon 161 listed in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Feb. 22, 2016). Specifically, there are 2 of 33,175 non-Finnish European individuals.

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