Description
The R190L pathogenic variant in the KCNQ1 gene has been reported multiple times in association with LQTS (Kapplinger et al., 2009; Kanovsky et al., 2010; Andrsova et al., 2012; Crehalet et al., 2012; Wang et al., 2015). Kanovsky et al. (2010) identified the R190L variant on both KCNQ1 alleles in two siblings with severe LQTS, one of whom had sub-clinical, bilateral hearing impairment that the authors termed incomplete" Jervell Lange-Nielsen syndrome. In the same study, the heterozygous parents of these two siblings had normal QT intervals at rest, but each parent had QT prolongation during stress testing (Kanovsky et al., 2010). R190L has been reported in combination with a KCNQ1 splice variant in a young male patient with LQTS (Crehalet et al., 2012). Additionally, Wang et al. (2015) identified R190L in conjunction with variants in the MYH7, MYLK2, and TMEM70 genes among four individuals in a Chinese family with overlapping phenotypes of LQTS and hypertrophic cardiomyopathy. R190L was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, and was not observed with any significant frequency in the Exome Aggregation Consortium (ExAC) data set.The R190L 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. Moreover, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Functional studies conducted by Eckey et al. (2014) demonstrated that R190L impairs phosphatidylinositol 4,5-bisphosphate (PIP2) regulation of ion channels, presumptively leading to ion channel dysfunction and LQTS phenotype. Finally, missense pathogenic variants in nearby residues, as well as in the same residue (G186S, R190W, R190Q) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), further supporting the functional importance of this region of the protein."
| # | 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 |
