ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.304G>A (p.Ala102Thr) (rs374618872)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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 (; 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 Health, Inc RCV001170619 SCV001347665 uncertain significance Cardiomyopathy 2018-11-30 criteria provided, single submitter clinical testing
Invitae RCV001238766 SCV001411595 uncertain significance Hypertrophic cardiomyopathy 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 102 of the TNNI3 protein (p.Ala102Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs374618872, ExAC 0.01%). This variant has been observed in an individual 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: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0. The threonine 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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