Description
The R894C variant of uncertain significance in the KCNH2 gene has been reported in one individual referred for LQTS testing (Kapplinger et al., 2009). Wang et al. (2014) identified R894C in a 38 year-old woman with sudden unexplained death and negative autopsy. The R894C variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R894C 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. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, a majority of splice-prediction algorithms predict that R894C creates a new cryptic splice donor site located upstream of natural splice donor site in intron 7; however, the new upstream donor site is predicted to be weaker than natural site. Lastly, a variant at this same residue (R894L) has been reported in HGMD in association with LQTS (Stenson et al., 2014), although the clinical significance of this variant has not been definitively determined. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | yes | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
