ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1873G>C (p.Val625Leu) (rs1563156725)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756284 SCV000884049 likely pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing The p.Val625Leu variant has not been reported in the medical literature, is not listed in gene-specific variant databases, nor has it been previously identified in our laboratory. It is also absent from population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Genome Aggregation Database (gnomAD) browser. The valine at codon 625 is highly conserved considering 14 species up to Tetraodon (Alamut software v2.9), and computational analyses suggest this variant has a significant effect on KCNH2 protein structure/function (SIFT: damaging, PolyPhen2probably damaging, and Mutation Taster: disease causing). Valine 625 is located in the pore region of KCNH2, and two other rare variants affecting this residue (p.Val625Ala and p.Val625Glu) have been reported in individuals included in long QT cohorts (Lieve 2013, Van Langen 2003, Giudicessi 2012). Additionally, several other rare variants in nearby amino acids have also been found in long QT patients (selected references: Kapplinger 2009, Splawski 2000, Kane 2014), and functional studies in cell culture have indicated that these variants (in addition to p.Val625Glu) impart trafficking defects to KCNH2 protein (Anderson 2014). Taken together, we interpret the p.Val625Leu variant to be likely pathogenic.

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