Submissions for variant NM_000238.4(KCNH2):c.2255G>A (p.Arg752Gln)

gnomAD frequency: 0.00001  dbSNP: rs121912512

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148536	SCV000253679	pathogenic	Long QT syndrome	2024-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 752 of the KCNH2 protein (p.Arg752Gln). This variant is present in population databases (rs121912512, gnomAD 0.008%). This missense change has been observed in individuals with long QT interval (PMID: 12621127, 34319147; Invitae). ClinVar contains an entry for this variant (Variation ID: 14435). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 12621127, 25417810). This variant disrupts the p.Arg752 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 11009462, 18441445). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001659699	SCV001875253	likely pathogenic	not provided	2024-07-04	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 (PMID: 12621127); Published functional studies demonstrate a damaging effect as this variant leads to significantly decreased channel function and causes a protein trafficking defect (PMID: 12621127, 25417810); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25417810, 25637381, 37324772, 34309407, 12621127, 34570182, 34319147)
Clinical Genomics Laboratory, Washington University in St. Louis	RCV000015516	SCV004176982	likely pathogenic	Long QT syndrome 2	2023-08-31	criteria provided, single submitter	clinical testing	The KCNH2 c.2255G>A (p.Arg752Gln) variant has been reported in two individuals affected with Long QT syndrome, one heterozygote (Choi SH et al., PMID: 34319147) and one homozygote (Johnson WH et al., PMID: 12621127). Johnson and colleagues make note that three family members to the homozygous patient were heterozygous for the p.Arg752Gln variant and were asymptomatic (Johnson WH et al., PMID: 12621127). The variant is only observed on 2 alleles out of 281,892 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Functional studies show that this variant leads to significantly decreased channel function and disrupts protein trafficking (Anderson CL et al., PMID: 25417810; Johnson WH et al., PMID: 12621127). Computational predictors indicate that the variant is damaging, evidence that correlates with impact to KCNH2 function. Another variant in the same codon, c.2254C>T (p.Arg752Trp), has been reported in affected individuals with Long QT and is considered pathogenic (Ficker E et al., PMID: 11009462; Itoh H et al., PMID: 26669661; Nagaoka I et al., PMID: 18441445; Splawski I et al., PMID: 10973849; Stattin EL et al., PMID: 23098067, ClinVar Variation ID: 67379). This variant has been reported in the ClinVar database as a pathogenic variant, a likely pathogenic variant, and a variant of uncertain significance by one submitter each in association for Long QT syndrome. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic.
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	flagged submission	research