ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.221_251del (p.Thr74fs) (rs1554430908)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000598913 SCV000710016 pathogenic not provided 2018-01-26 criteria provided, single submitter clinical testing The c.221_251del31 pathogenic variant in the KCNH2 gene (also reported as R73fs/31 due to alternate nomenclature) has been reported previously in association with LQTS (Splawski et al., 2000; Tester et al., 2005; Johnson et al., 2009). Additionally, the c.221_251del31 variant has been identified in another unrelated individual referred for LQTS genetic testing at GeneDx. Furthermore, this variant has not been observed in large population cohorts (Lek et al., 2016). This variant causes a shift in reading frame starting at codon threonine (Thr) 74, changing it to a arginine (Arg), and creating a premature stop codon at position 32 of the new reading frame, denoted p.Thr74ArgfsX32. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the KCNH2 gene have been reported in Human Gene Mutation Database in association with LQTS (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene.
Invitae RCV000631615 SCV000752697 pathogenic Long QT syndrome 2017-12-04 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. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with KCNH2-related disease. Loss-of-function variants in KCNH2 are known to be pathogenic (PMID: 19862833). For these reasons, this variant has been classified as Pathogenic.

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