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

gnomAD frequency: 0.00001  dbSNP: rs753413305

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000535232	SCV000623785	uncertain significance	Hypertrophic cardiomyopathy	2023-09-08	criteria provided, single submitter	clinical testing	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 454406). This variant has not been reported in the literature in individuals affected with TNNI3-related conditions. This variant is present in population databases (rs753413305, gnomAD 0.002%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 161 of the TNNI3 protein (p.Ala161Val).
Color Diagnostics, LLC DBA Color Health	RCV001188384	SCV001355440	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 161 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with hypertrophic cardiomyopathy (PMID: 33495597). This variant has been identified in 2/248904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002341249	SCV002635083	uncertain significance	Cardiovascular phenotype	2022-03-28	criteria provided, single submitter	clinical testing	The p.A161V variant (also known as c.482C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 482. The alanine at codon 161 is replaced by valine, an amino acid with similar properties. This variant was reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Harper AR et al. Nat Genet, 2021 02;53:135-142). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000535232	SCV004819054	uncertain significance	Hypertrophic cardiomyopathy	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 161 of the TNNI3 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with hypertrophic cardiomyopathy (PMID: 33495597). This variant has been identified in 2/248904 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
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.