Submissions for variant NM_000238.4(KCNH2):c.3112G>A (p.Val1038Met)

gnomAD frequency: 0.00006  dbSNP: rs199473544

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181911	SCV000234214	likely benign	not provided	2021-05-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19716085, 28988457)
Invitae	RCV001088304	SCV000543432	likely benign	Long QT syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000987996	SCV001137539	benign	Long QT syndrome 2	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841744	SCV001356093	uncertain significance	Cardiac arrhythmia	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1038 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT testing (PMID: 19716085). This variant has been identified in 20/175942 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804794	SCV002051248	likely benign	not specified	2021-12-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003894913	SCV004714113	likely benign	KCNH2-related condition	2023-10-12	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV001088304	SCV004835855	uncertain significance	Long QT syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with methionine at codon 1038 of the KCNH2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT testing (PMID: 19716085). This variant has been identified in 20/175942 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.
Ambry Genetics	RCV004019015	SCV005033313	benign	Cardiovascular phenotype	2023-09-29	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058199	SCV000089719	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.