ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.1280A>C (p.Tyr427Ser) (rs199472897)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000246613 SCV000319053 likely pathogenic Cardiovascular phenotype 2013-10-30 criteria provided, single submitter clinical testing The p.Y427S variant (also known as c.1280A>C) is located in coding exon 6 of theKCNH2gene. This alteration results from an A to C substitution at nucleotide position 1280. The tyrosine at codon 427 is replaced by serine, an amino acid with some dissimilar properties.This alteration is located in the S1/S2 transmembrane domain of HERGand was detected in one of 388 individuals with a diagnosis of Long QT syndrome (LQTS) yet absent in >2600 control alleles studied. Authors noted that all rare single nucleotide variants in the transmembrane domain were identified in cases only and completely absent from the control cohort (Kapa S et al.Circulation.2009;120:1752-1760). Variants at this same codon with an alternate amino acid substitution have also been reported inpatientswith LQTS, including one individual with a p.Y427C alteration and two individuals with a p.Y427H alteration (Kapplinger JD et al.Heart Rhythm 2009;6:1297-1230;Millat G et al.Clin Genet. 2006;70:214-227​;Napolitano C et al. JAMA. 2005;294:2975-2980).​This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), the 1000 Genomes Project and the NHLBI Exome Sequencing Project (ESP). In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000246613 SCV000696017 likely pathogenic Cardiovascular phenotype 2016-11-07 criteria provided, single submitter clinical testing Variant summary: The KCNH2 c.1280A>C (p.Tyr427Ser) variant involves the alteration of a highly conserved nucleotide and is located in the ion transport domain at S1-S4 transmembrane region (InterPro, Itoh_2016). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 125938 control chromosomes, including the large and broad populations from ExAC. This variant has been reported as a pathogenic variant in literature found in at least two LQTS families; and in one family, the variant was found to be paternally inherited (Tester_2005, Kapa_2009, Giudicessi_2012, Itoh_2010, Itoh_2016). Other missense variants such as p.Tyr427His (PMIDs: 16414944, 16922724, and 22581653) and p.Tyr427Cys (PMIDs: 19716085 and 22581653) have also been reported in this codon, indicating that the codon is in a mutational hot-spot. One clinical diagnostic laboratory has classified this variant as likely pathogenic. Taken together, this variant is classified as Likely Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057885 SCV000089405 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:15840476;PMID:19841300). 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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