Submissions for variant NM_000238.4(KCNH2):c.157G>C (p.Gly53Arg)

dbSNP: rs199472842

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001841702	SCV000913628	likely pathogenic	Cardiac arrhythmia	2019-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 53 in the cytoplasmic N-terminal PAS domain of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies have shown that the mutant protein is defective for protein maturation and trafficking to the cell surface (PMID: 22396785, 25417810, 26958806), but shows normal function if successfully transported to the cell surface (PMID: 26958806). This variant has been reported in multiple long QT syndrome patients (PMID: 10973849, 15635208 15840476) and may also present as concealed long QT syndrome (PMID: 21185501). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant at the same position (p.Gly53Asp) has also been observed in a long QT syndrome patient (PMID: 19716085). Based on the available evidence, this variant is classified as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001267970	SCV001446513	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001267970	SCV002504263	pathogenic	not provided	2022-01-13	criteria provided, single submitter	clinical testing	Identified in patients with LQTS in the published literature and in a patient with LQTS referred for genetic testing at GeneDx (Splawski et al., 2000; Tester et al., 2005); Not observed in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via channel deactivation or trafficking defect (Chen et al., 1999; Harley et al., 2012; Anderson et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 67215); This variant is associated with the following publications: (PMID: 10187793, 15840476, 21536673, 23303164, 22396785, 32475984, 10973849, 25417810)
Ambry Genetics	RCV002399419	SCV002710098	likely pathogenic	Cardiovascular phenotype	2020-09-25	criteria provided, single submitter	clinical testing	The p.G53R variant (also known as c.157G>C), located in coding exon 2 of the KCNH2 gene, results from a G to C substitution at nucleotide position 157. The glycine at codon 53 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in a patient with Long QT Syndrome Type 2 (LQT2) (Haraguchi Y et al. Circ. J., 2005 Jan;69:78-82). Functional studies indicate that this alteration will impact protein function (Chen J et al. J. Biol. Chem., 1999 Apr;274:10113-8; Gianulis EC et al. J. Biol. Chem., 2011 Jun;286:22160-9; Anderson CL et al. Nat Commun, 2014 Nov;5:5535). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this alteration is located within the PAS domain of KCNH2 and is expected to disrupt trafficking and lead to deactivation of the potassium channel (Chen J et al. J. Biol. Chem., 1999 Apr;274:10113-8; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000057924	SCV004848212	likely pathogenic	Congenital long QT syndrome	2018-05-14	criteria provided, single submitter	clinical testing	The p.Gly53Arg variant in KCNH2 has been reported in at least 4 individuals with Long QT syndrome (LQTS; Splawski 2000, Haraguchi 2005, Tester 2005, Goldenberg 2011), and was absent from large population studies. In vitro functional studies provide some evidence that the p.Gly53Arg variant may impact protein trafficking, although effects of the variant on gating potential are conflicting (Chen 1999, Gianulis 2011, Harley 2012, Anderson 2014). An animal model in zebrafish has shown that this variant cannot rescue wildtype levels of repolorization (Jou 2013). Note, these types of assays may not accurately represent biological function. This variant has been reported in ClinVar (Variation ID: 67215). Computational prediction tools and conservation analysis suggest that the p.Gly53Arg variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly53Arg variant is likely pathogenic. ACMG/AMP Criteria applied: PS3_Moderate, PM2, PS4_Supporting, PP3.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000057924	SCV000089444	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:10187793;PMID:10973849;PMID:15840476;PMID:21536673;PMID:22396785). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.