Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000498554 | SCV000589516 | pathogenic | not provided | 2017-09-28 | criteria provided, single submitter | clinical testing | A published K273E variant that is pathogenic was identified in the TNNT2 gene. Fujino et al. (2002) observed the K273E variant segregated with HCM in two families. In the first family, K273E segregated in five living individuals with HCM and there were multiple untested family members with sudden death, one of whom is an obligate carrier of the variant based on pedigree structure. In the second family, K273E was observed in four individuals with HCM over three generations (Fujino et al., 2002). Additionally, the K273E variant is not observed in large population cohorts (Lek et al., 2016), indicating it is not a common benign variant.The K273E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties and this substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, functional studies suggest K273E increases muscle fiber Ca2+ sensitivity and was completely uncoupled from troponin-I phosphorylation levels, a similar effect to other TNNT2 pathogenic variants (Venkatraman et al., 2003; Messer et al., 2016).In summary, K273E in the TNNT2 gene is interpreted as a pathogenic variant. |