Submissions for variant NM_000238.4(KCNH2):c.298C>T (p.Arg100Trp)

dbSNP: rs121912515

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001230350	SCV001402825	uncertain significance	Long QT syndrome	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 100 of the KCNH2 protein (p.Arg100Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, 24217263, 36861347; internal data). ClinVar contains an entry for this variant (Variation ID: 67459). 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: 25417810, 32475984, 35688148). This variant disrupts the p.Arg100 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been observed in individuals with KCNH2-related conditions (PMID: 16922724), which suggests that this may be a clinically significant amino acid residue. 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.
Ambry Genetics	RCV002433560	SCV002746387	likely pathogenic	Cardiovascular phenotype	2021-01-13	criteria provided, single submitter	clinical testing	The p.R100W variant (also known as c.298C>T), located in coding exon 2 of the KCNH2 gene, results from a C to T substitution at nucleotide position 298. The arginine at codon 100 is replaced by tryptophan, an amino acid with dissimilar properties, and is located in the PAC protein domain. Immunoblot data along with computational structural models suggest that this variant is a protein trafficking deficient alteration (Anderson CL et al. Nat Commun, 2014 Nov;5:5535). In a study of long QT syndrome clinical genetic testing, this alteration was reported in two patients; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). Based on internal structural analysis, this variant is predicted to be structurally destabilizing. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. 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.
All of Us Research Program, National Institutes of Health	RCV001230350	SCV004844076	uncertain significance	Long QT syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 100 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least one individual affected with long QT syndrome (doi:10.14288/1.0406222) and in 2 individuals with suspected long QT syndrome (PMID: 19716085). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058187	SCV000089707	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.