Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000494218 | SCV000583009 | uncertain significance | not provided | 2017-05-24 | criteria provided, single submitter | clinical testing | Although the D190E variant of uncertain significance in the TNNI3 gene has not been published as pathogenic or been reported as benign to our knowledge, variants affecting the same residue (D190G, D190Y) have been reported in association with RCM and HCM (Mogensen et al., 2003; Walsh et al., 2017). However, while the D190G and D190Y variants are non-conservative amino acid substitution, which are likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties, the D190E variant is conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Nevertheless, the D190E variant occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, missense variants in nearby residues (R186Q, R192H, N194S) have been reported in the Human Gene Mutation Database in association with HCM and RCM (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Furthermore, the D190E variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Despite this, the D190E variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. |