ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.221C>G (p.Thr74Arg) (rs199473422)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182051 SCV000234354 pathogenic not provided 2011-11-07 criteria provided, single submitter clinical testing The Thr74Arg mutation in the KCNH2 gene has been reported previously in association with LQTS. Kapplinger et al. identified Thr74Arg in one patient with LQTS and reported that this change was absent from more than 2,600 control alleles. Thr74Arg results in a non-conservative amino acid substitution of a neutral Threonine with a positively charged Arginine at a position that is conserved throughout evolution. Furthermore, mutations in the Thr74 codon (Thr74Pro, Thr74Met) and in surrounding codons (Gly71Arg, Pro72Arg, Pro72Gln, Pro72Leu, Ala78Pro) have been reported in association with LQTS, further supporting the functional importance of this region of the protein. Therefore, the presence of Thr74Arg in the KCNH2 gene is consistent with a diagnosis of LQTS. The variant is found in LQT panel(s).
Invitae RCV001060143 SCV001224810 uncertain significance Long QT syndrome 2019-12-14 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 74 of the KCNH2 protein (p.Thr74Arg). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67376). This variant has been reported to affect KCNH2 protein function (PMID: 25417810). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058096 SCV000089616 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:19716085). 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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