ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.538G>A (p.Asp180Asn) (rs1060503103)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000472513 SCV000551897 uncertain significance Hypertrophic cardiomyopathy 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 180 of the TNNI3 protein (p.Asp180Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV001254755 SCV001430848 uncertain significance Primary dilated cardiomyopathy 2019-06-04 no assertion criteria provided research TNNI3 Asp180Asn has been previously reported in a childhood DCM case (Genedx, ClinVar: SCV000551897.1). We identified this variant in one DCM proband, the variant was also found to segregate to an affected family member. This variant is absent from the Genome Aggregation Database (http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen-2 and MutationTaster predict this variant to be deleterious. In summary, the variant has been reported in one other DCM case, is rare in the general population and in silico tools predict that the variant impacts protein function, therefore we classify TNNI3 Asp180Asn as a variant of 'uncertain significance'.

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