Submissions for variant NM_000238.4(KCNH2):c.2771G>C (p.Gly924Ala)

dbSNP: rs199473009

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000454684	SCV000539441	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468983	SCV000543457	uncertain significance	Long QT syndrome	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 924 of the KCNH2 protein (p.Gly924Ala). 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 testing and/or epilepsy (PMID: 19716085, 26704558, 34002542). ClinVar contains an entry for this variant (Variation ID: 67438). 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"). Experimental studies have shown that this missense change affects KCNH2 function (PMID: 34002542). 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	RCV000619828	SCV000735945	likely benign	Cardiovascular phenotype	2023-03-24	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.
Color Diagnostics, LLC DBA Color Health	RCV001841725	SCV001355730	uncertain significance	Cardiac arrhythmia	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine 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). A functional study has shown that this variant causes a significant reduction in current amplitude (PMID: 34002542). This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085) and in an individual affected with sudden unexpected death in epilepsy (PMID: 26704558, 34002542). This variant has been identified in 8/158560 chromosomes 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198823	SCV001369818	uncertain significance	Short QT syndrome type 1	2020-01-30	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM1,BP4.
All of Us Research Program, National Institutes of Health	RCV000468983	SCV004835935	uncertain significance	Long QT syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with alanine 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). A functional study has shown that this variant causes a significant reduction in current amplitude (PMID: 34002542). This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085) and in an individual affected with sudden unexpected death in epilepsy (PMID: 26704558, 34002542). This variant has been identified in 8/158560 chromosomes 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	RCV000058164	SCV000089684	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.