Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000472513 | SCV000551897 | uncertain significance | Hypertrophic cardiomyopathy | 2018-09-11 | 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. 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. 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"). 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. |
| Ambry Genetics | RCV002348329 | SCV002642819 | uncertain significance | Cardiovascular phenotype | 2022-07-07 | criteria provided, single submitter | clinical testing | The p.D180N variant (also known as c.538G>A), located in coding exon 7 of the TNNI3 gene, results from a G to A substitution at nucleotide position 538. The aspartic acid at codon 180 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Agnes Ginges Centre for Molecular Cardiology, |
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'. |