ClinVar

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNH2 p.Pro1034fs This variant is novel, it has not been reported in peer reviewed literature in association with disease. However, many similar variants at this and neighboring codons have been reported with long QT syndrome. This is a four nucleotide duplication which alters the reading frame essential for complete protein synthesis. This typically leads to a premature stop codon downstream. These variants typically lead either to a truncated protein or to no expressed protein at all, due to nonsense mediated mRNA decay. If a premature stop codon is not created (which is unlikely), then this variant would lead to a protein with a completely different amino acid sequence after codon 1034. While p.Pro1034fs has not been reported before several additional frameshift variants have been identified at this codon or in nearby codons in individuals with long QT syndrome: p. Pro1034GlyfsX83 (Kapplinger et al 2009), p.Pro1034fs+18X (Kapplinger et al 2009), p.Pro1034fx+21X (Kapplinger et al 2009), p.Pro1034fx+83X (Kapplinger et al 2009), p.Pro1034ArgfsX82, p.Pro1034ArgfsX81 (Tester et al 2005), p.Pro1034ProfsX23 (Napolitano et al 2005), p.Gly1031fs+86X (Napolitano et al 2005), p.Gly1031fs+20X (Napolitano et al 2005), p.Gly1031+24X (Splawski et al 200), p.Arg1032fs (Millat et al 2006), etc. In addition, many other frameshift and nonsense variants at other locations in the KCNH2 gene have been implicated in long QT syndrome. In the Familion case series, they did not see the variant in 1300 presumably healthy individuals of mixed ancestry (published in Kapa et al 2009).