ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.3003G>A (p.Trp1001Ter)

dbSNP: rs121912509
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181905 SCV000234208 pathogenic not provided 2024-10-06 criteria provided, single submitter clinical testing Has been reported in individuals with LQTS (PMID: 11854117, 23995044); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest the p.(W1001*) variant results in a truncated protein and significant reduction in channel current properties (PMID: 12021266); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 11686910, 11854117, 23995044, 17576861, 12021266)
Labcorp Genetics (formerly Invitae), Labcorp RCV001207958 SCV001379326 pathogenic Long QT syndrome 2019-08-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this nonsense change (p.Tryp1001*) results in reduced mRNA levels due to nonsense-mediated decay and the resulting protein is truncated, which results in a channel with reduced current amplitude (PMID: 17576861, 12021266). Loss-of-function variants in KCNH2 are known to be pathogenic. There are two different nucleotide changes (c.3002G>A and c.3003G>A) that result in the same amino acid change to a stop codon. The variant c.3002G>A has been classified as pathogenic (Invitae database). This protein change has been reported in the literature in individuals affected with long QT syndrome (PMID: 12021266, 26846766, 11854117). This sequence change creates a premature translational stop signal at codon 1001 (p.Trp1001*) of the KCNH2 gene. It is expected to result in an absent or disrupted protein product.
OMIM RCV000015512 SCV000035777 pathogenic Long QT syndrome 2 2002-07-26 no assertion criteria provided literature only

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