ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.2255G>A (p.Arg752Gln) (rs121912512)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000148536 SCV000253679 likely pathogenic Long QT syndrome 2015-04-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 752 of the KCNH2 protein (p.Arg752Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant has been reported in the literature and is present in population databases (rs121912512, <0.01%). It was reported in the homozygous state in a case of infantile long QT syndrome that presented in utero. ClinVar contains entries for this variant (RCV000058100, RCV000015516, RCV000148536). Experimental studies have shown that this missense change does not transmit current vitro and is also trafficking deficient (PMID: 12621127, 25417810). A different missense substitution at this codon, p.Arg752Trp, is considered Pathogenic for long QT syndrome (PMID: 11854117, 16432067, 18441445, 23098067, 25417810). This indicates that the arginine residue at this position is important for KCNH2 protein function. In summary, this is a rare variant that has been observed in the homozygous state in a case of early onset long QT syndrome and it affects an amino acid that is known to be necessary for normal protein activity. As a result, this variant has been classified as Likely Pathogenic.
GeneDx RCV001659699 SCV001875253 likely pathogenic not provided 2021-07-29 criteria provided, single submitter clinical testing Reported as a homozygous variant in a patient with Long QT syndrome diagnosed in utero; however, heterozygous family members had normal QT intervals (Johnson et al., 2003); Reported in ClinVar as a likely pathogenic variant (ClinVar Variant ID# 14435; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect as this variant leads to significantly decreased channel function and causes a protein trafficking defect (Johnson et al., 2003; Anderson et al., 2014); This variant is associated with the following publications: (PMID: 12621127, 25637381, 25417810)
OMIM RCV000015516 SCV000035781 pathogenic Long QT syndrome 2 2003-05-01 no assertion criteria provided literature only
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058100 SCV000089620 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:12621127). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
CSER _CC_NCGL, University of Washington RCV000148536 SCV000190249 uncertain significance Long QT syndrome 2014-06-01 no assertion criteria provided research

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