ClinVar Miner

Submissions for variant NM_172057.2(KCNH2):c.2074del (p.Arg692fs) (rs864622309)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000204772 SCV000260083 pathogenic Long QT syndrome 2016-06-24 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide in exon 13 of the KCNH2 mRNA (c.3094delC), causing a frameshift at codon 1032. This creates a premature translational stop signal (p.Arg1032Glyfs*25) and is expected to result in an absent or disrupted protein product. Truncating variants in KCNH2 are known to be pathogenic. This particular truncation has been reported in one individual affected with long QT syndrome (PMID: 10973849) and has been shown to elicit nonsense mediated decay (PMID: 24530480). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000413486 SCV000491458 pathogenic not provided 2017-11-24 criteria provided, single submitter clinical testing The c.3094delC pathogenic variant in the KCNH2 gene has been reported previously in at least one individual with LQTS, and was absent from 2,600 control alleles (Splawski et al., 2000; Kapplinger et al., 2009). It is also reported as a pathogenic variant in ClinVar by a different clinical laboratory in association with LQTS (ClinVar SCV000260083.1; Landrum et al., 2016). This variant causes a shift in reading frame starting at codon Arginine 1032, changing it to a Glycine, and creating a premature stop codon at position 25 of the new reading frame, denoted p.Arg1032GlyfsX25. Functional studies have shown that this pathogenic variant results in a loss of protein expression from this allele through nonsense-mediated mRNA decay (Gong et al., 2014). Other frameshift variants in the KCNH2 gene have been reported in the Human Gene Mutation Database in association with LQTS (Stenson et al., 2014). In summary, c.3094delC in the KCNH2 gene is interpreted as a pathogenic variant.
Ambry Genetics RCV000621802 SCV000737698 pathogenic Cardiovascular phenotype 2016-08-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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