ClinVar Miner

Submissions for variant NM_000238.4(KCNH2):c.221_251del (p.Thr74fs)

dbSNP: rs1554430908
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598913 SCV000710016 pathogenic not provided 2019-10-02 criteria provided, single submitter clinical testing Reported in ClinVar as a pathogenic variant by another clinical laboratory (ClinVar Variant ID# 503735; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Frameshift 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: 10973849, 15840476, 19038855)
Labcorp Genetics (formerly Invitae), Labcorp RCV000631615 SCV000752697 pathogenic Long QT syndrome 2023-12-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Thr74Argfs*32) in the KCNH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 10973849, 19862833). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 503735). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000631615 SCV004813517 pathogenic Long QT syndrome 2024-02-20 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.221_251del31 (p.Thr74ArgfsX32) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 228884 control chromosomes (gnomAD). c.221_251del31 has been reported in the literature in individuals affected with Long QT Syndrome (e.g. Shimizu_2009). These data indicate that the variant is likely associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 19926013). ClinVar contains an entry for this variant (Variation ID: 503735). Based on the evidence outlined above, the variant was classified as pathogenic.

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