Submissions for variant NM_000238.4(KCNH2):c.2771G>A (p.Gly924Glu)

dbSNP: rs199473009

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000251484	SCV000319532	likely benign	Cardiovascular phenotype	2024-02-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000817376	SCV000957931	uncertain significance	Long QT syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 924 of the KCNH2 protein (p.Gly924Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, 23338923). ClinVar contains an entry for this variant (Variation ID: 67437). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics	RCV000987999	SCV001137543	uncertain significance	Long QT syndrome 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841724	SCV001349229	uncertain significance	Cardiac arrhythmia	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 924 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 23338923) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 10/158560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000817376	SCV004835936	uncertain significance	Long QT syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 924 of the KCNH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with long QT syndrome (PMID: 23338923) and in an individual referred for long QT syndrome genetic testing (PMID: 19716085). This variant has been identified in 10/158560 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary 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	RCV000058163	SCV000089683	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.
GeneDx	RCV000181891	SCV000234194	pathogenic	not provided	2015-03-12	flagged submission	clinical testing	p.Gly924Glu (GGG>GAG): c.2771 G>A in exon 12 of the KCNH2 (aka HERG) gene (NM_000238.2)The Gly924Glu mutation in the KCNH2 gene has been reported in one patient with LQTS and it was absent from 2,600 reference alleles (Kapplinger J et al., 2009). Additionally, the NHLBI ESP Exome Variant Server reports Gly924Glu was not observed in approximately 3,700 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Gly924Glu results in a non-conservative amino acid substitution of a non-polar Glycine with a negatively charged Glutamic acid. Mutations at this residue (Gly924Ala) and in nearby residues (Arg922Trp, Arg922Gln, Gly925Arg) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein.In summary, Gly924Glu in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in POSTMORTEM panel(s).