ClinVar Miner

Submissions for variant NM_000238.3(KCNH2):c.2843G>A (p.Arg948His) (rs199473011)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058170 SCV000089690 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:20541041). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GeneDx RCV000182047 SCV000234350 pathogenic not provided 2011-10-18 criteria provided, single submitter clinical testing The Arg948His mutation in the KCNH2 gene has been published previously in a single individual from a cohort of Japanese patients with LQTS, and was not detected in 400 control alleles from the same population. Other amino acid substitutions affecting the same codon (Arg948Ser, Arg948Cys) and nearby codons (Ser937Asn, Leu955Val) have also been reported in association with LQTS, further supporting the functional importance of this position and this region of the protein. In addition, Arg948His was not detected in 308 control alleles from individuals of various ethnic backgrounds tested at GeneDx, indicating it is not a common benign variant in these populations. In summary, the presence of Arg948His in the KCNH2 gene is consistent with a diagnosis of LQTS. The variant is found in LQT panel(s).
Institute of Human Genetics,Klinikum rechts der Isar RCV000578446 SCV000680268 likely pathogenic Long QT syndrome 2 2017-12-09 criteria provided, single submitter clinical testing
Invitae RCV000794762 SCV000934189 uncertain significance Long QT syndrome 2018-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 948 of the KCNH2 protein (p.Arg948His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs199473011, ExAC 0.1%). This variant has been observed in an individual affected with long QT syndrome (PMID: 20541041). ClinVar contains an entry for this variant (Variation ID: 67443). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The observation of one or more missense substitutions at this codon (p.Arg948Ser) in an affected individual suggests that this may be a clinically significant residue (PMID: 20541041). 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.

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