Submissions for variant NM_000363.5(TNNI3):c.304G>A (p.Ala102Thr)

gnomAD frequency: 0.00003  dbSNP: rs374618872

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152087	SCV000200729	likely benign	not specified	2013-09-24	criteria provided, single submitter	clinical testing	Ala102Thr in exon 6 of TNNI3: This variant is not expected to have clinical sign ificance due to a lack of conservation across species, including mammals. Of not e, 4 mammals (marmoset, kangaroo rat, guinea pig, squirrel) have a threonine (Th r) at this position, despite high nearby amino acid conservation. In addition, c omputational analyses (AlignGVGD, PolyPhen2, SIFT) do not suggest a high likelih ood of impact to the protein. This variant has also been identified in 1/4224 Af rican American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs. washington.edu/EVS/; dbSNP rs374618872).
GeneDx	RCV000152087	SCV000730183	likely benign	not specified	2017-04-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170619	SCV001333209	uncertain significance	Cardiomyopathy	2018-06-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170619	SCV001347665	uncertain significance	Cardiomyopathy	2023-05-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 102 of the TNNI3 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 28771489). This variant has also been identified in 5/280854 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.
Invitae	RCV001238766	SCV001411595	uncertain significance	Hypertrophic cardiomyopathy	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 102 of the TNNI3 protein (p.Ala102Thr). This variant is present in population databases (rs374618872, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of hypertrophic cardiomyopathy (PMID: 28771489). ClinVar contains an entry for this variant (Variation ID: 165521). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV002444628	SCV002754118	uncertain significance	Cardiovascular phenotype	2021-10-28	criteria provided, single submitter	clinical testing	The p.A102T variant (also known as c.304G>A), located in coding exon 6 of the TNNI3 gene, results from a G to A substitution at nucleotide position 304. The alanine at codon 102 is replaced by threonine, an amino acid with similar properties. This variant was reported in two individuals from a hypertrophic cardiomyopathy cohort; however, clinical details were limited, and additional cardiac variants were also detected (Mademont-Soler I et al. PLoS One, 2017 Aug;12:e0181465). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.