ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.421C>T (p.Arg141Trp) (rs730881071)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159219 SCV000209165 likely pathogenic not provided 2016-09-19 criteria provided, single submitter clinical testing A R141W variant that is likely pathogenic was identified in the TNNI3 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The R141W variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R141W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is class conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Mutations in this same residue (R141Q) and nearby residues (R136Q, T143N) have been reported in association with cardiomyopathy, supporting the functional importance of this residue and this region of the protein.Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in DCM-CRDM panel(s).
Invitae RCV000473123 SCV000551894 uncertain significance Hypertrophic cardiomyopathy 2019-08-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 141 of the TNNI3 protein (p.Arg141Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs730881071, ExAC 0.002%). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 29121657). ClinVar contains an entry for this variant (Variation ID: 181580). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg141 amino acid residue in TNNI3. Other variant(s) that disrupt this residue have been observed in individuals with TNNI3-related conditions (PMID: 12707239, 15607392, 18403758, 19645627, 22429680, 22876777, 23283745, 25524337), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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