ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.1394T>G (p.Phe465Cys) (rs199472999)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181862 SCV000234165 pathogenic not provided 2013-04-16 criteria provided, single submitter clinical testing p.Phe805Cys (TTT>TGT): c.2414 T>G in exon 10 of the KCNH2 gene (NM_000238.2)The Phe805Cys mutation in the KCNH2 gene has been reported previously in one individual diagnosed with LQTS (Splawski I et al., 2000). Functional studies have shown that Phe805Cys results in a trafficking defect and consequent reduced potassium channel current (Ficker E et al., 2002; Anderson C et al., 2006). Also, a mutation affecting this same residue, Phe805Ser, has been reported in association with LQTS and was absent from more than 400 control alleles in this study (Splawski I et al., 2000). Mutations in nearby residues (Gly800Glu, Gly800Trp, Gly806Glu) have been reported in association with LQTS, supporting the functional importance of this residue and this region of the protein. Furthermore, Phe805Cys was not observed in approximately 6500 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, Phe805Cys in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Invitae RCV000474113 SCV000543449 likely pathogenic Long QT syndrome 2016-12-25 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 805 of the KCNH2 protein (p.Phe805Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (rs199472999, ExAC no frequency). This variant has been reported in a family affected with long QT syndrome (PMID: 11854117). ClinVar contains an entry for this variant (Variation ID: 67397). This variant identified in the KCNH2 gene is located in the cytoplasmic cyclic nucleotide binding region of the resulting protein (PMID: 19841300). For more information about the location of this variant, please visit Experimental studies have shown that this variant affects protein trafficking and therefore potassium channel current (PMID: 16432067, 23303164, 11741928, 12837749) For these reasons, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000621445 SCV000738081 likely pathogenic Cardiovascular phenotype 2017-07-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058119 SCV000089639 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:10973849;PMID:11854117;PMID:15840476;PMID:16432067;PMID:18468596;PMID:11741928). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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