ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.512C>T (p.Ala171Val) (rs1555863491)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000555081 SCV000623789 uncertain significance Hypertrophic cardiomyopathy 2017-04-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 171 of the TNNI3 protein (p.Ala171Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. 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. Missense variants that are absent from the ExAC population database have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). 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. A different missense substitution at this codon (p.Ala171Thr) has been determined to be pathogenic (PMID: 12531876, 15961398, 16288990, 18423659, 27532257). This suggests that the alanine residue is critical for TNNI3 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant is a novel missense change that affects a residue important for protein function. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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