ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.451G>A (p.Ala151Thr) (rs730881072)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159224 SCV000209170 likely pathogenic not provided 2013-09-26 criteria provided, single submitter clinical testing The Ala151Thr mutation in the TNNI3 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Ala151Thr results in a non-conservative amino acid substitution of a non-polar Alanine residue with a polar Threonine residue at a position that is conserved in mammals. In silico analysis predicts Ala151Thr is probably damaging to the protein structure/function. Mutations in nearby residues (Arg145Gln, Arg145Gly, Arg145Trp, Ser150Cys, Ala157Val) have been reported in association with HCM, supporting the functional importance of this region of the protein. Furthermore, Ala151Thr was not observed in approximately 6,000 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 Ala151Thr mutation also has been observed in other unrelated individual tested for HCM at GeneDx. The variant is found in DCM panel(s).
Invitae RCV000551025 SCV000623783 uncertain significance Hypertrophic cardiomyopathy 2017-04-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 151 of the TNNI3 protein (p.Ala151Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TNNI3-related disease. ClinVar contains an entry for this variant (Variation ID: 181581). 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. In summary, this variant is a rare missense change with uncertain impact on 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.

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