ClinVar

Description

p.Pro334Leu (CCC>CTC): c.1001 C>T in exon 5 of the KCNH2 gene (NM_000238.2). The P334L variant in the KCNH2 gene has been reported in association with LQTS (Lupoglazoff et al., 2001; Imboden et al., 2006). The P334L was identified as a novel mutation in 1 out of 57 affected individual with LQTS, and was absent from 150 control chromosomes (Lupoglazoff et al., 2001). Additionally, of the 240 families of European ancestry with LQTS studied by Imoboden et al., 2006, one family was reported to harbor the P334L mutation. The P334L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. 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. Missense mutations in nearby residues (R328C, D342V) have been reported in association with LQTS, supporting the functional importance of this region of the protein. Furthermore, the P334L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, P334L in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).