Submissions for variant NM_000238.4(KCNH2):c.1910AGA[1] (p.Lys638del)

dbSNP: rs794728442

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181980	SCV000234283	likely pathogenic	not provided	2017-01-03	criteria provided, single submitter	clinical testing	The c.1913_1915delAGA variant in the KCNH2 gene has been previously reported in association with LQTS (Splawski et al., 2000; Kapplinger et al., 2009), and was absent from approximately 2,600 control alleles (Kapplinger et al., 2009). Furthermore, the c.1913_1915delAGA 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. Located in the S6 segment of the KCNH2 gene, pathogenic variants in this region are expected to disrupt potassium transport (Splawski et al., 2000).Therefore, this variant is likely pathogenic
Invitae	RCV000456814	SCV000543450	likely pathogenic	Long QT syndrome	2022-07-25	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects KCNH2 function (PMID: 25417810). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 200646). This variant has been observed in individuals with long QT syndrome (PMID: 10973849, 26831020; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This variant, c.1913_1915del, results in the deletion of 1 amino acid(s) of the KCNH2 protein (p.Lys638del), but otherwise preserves the integrity of the reading frame.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV001248785	SCV001422295	likely pathogenic	Long QT syndrome 2	2020-02-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408790	SCV002720580	likely pathogenic	Cardiovascular phenotype	2018-04-04	criteria provided, single submitter	clinical testing	The c.1913_1915delAGA variant (also known as p.K638del) is located in coding exon 7 of the KCNH2 gene. This variant results from an in-frame deletion of 3 nucleotides at positions 1913 to 1915. This results in the deletion of a highly conserved lysine at codon 638, which is located in the pore/S6 region of the protein. This alteration has been reported in multiple subjects referred for long QT syndrome (LQTS) genetic testing and has been shown to segregate with disease in one family (Splawski I et al. Circulation, 2000 Sep;102:1178-85; Nagaoka I et al. Circ. J., 2008 May;72:694-9; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Ozawa J et al. Circ. J., 2016 Jan;80:696-702; Ichikawa M et al. Intern. Med., 2016 Feb;55:259-62). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic.