Submissions for variant NM_000238.4(KCNH2):c.2617G>A (p.Gly873Ser)

gnomAD frequency: 0.00079  dbSNP: rs41314354

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000171755	SCV000055201	likely benign	Brugada syndrome	2013-06-24	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083512	SCV000283974	likely benign	Long QT syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841711	SCV000913715	likely benign	Cardiac arrhythmia	2018-10-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194444	SCV001364007	benign	not specified	2019-03-31	criteria provided, single submitter	clinical testing	Variant summary: KCNH2 c.2617G>A (p.Gly873Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 278760 control chromosomes (gnomAD and publications), predominantly at a frequency of 0.0023 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 23 fold of the estimated maximal expected allele frequency for a pathogenic variant in KCNH2 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. Verkerk et al. (2005) reported c.2617G>A in a patient affected with Brugada syndrome and carried out functional assessments to determine the effect of the variant on protein function. A a negative shift of voltage-dependent inactivation resulting in increased rectification was noted and increased transient peak currents of the ventricular action potential were described. These results do not support an association of this finding with the established pathophysiology of disease in LQT2 (decreased rapid delayed rectifier potassium current) and Brugada syndrome (KCNH2 is not widely recognized as a gene causative of Brugada syndrome). Therefore, these findings do not provide unequivocal conclusions about association of the variant with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000058144	SCV001771677	likely benign	not provided	2020-11-17	criteria provided, single submitter	clinical testing	Reported in association with Brugada syndrome and hypertrophic cardiomyopathy (Verkerk et al., 2005; Lopes et al., 2015); Also observed in multiple control individuals and individuals who underwent genetic testing for indications unrelated to cardiomyopathy, arrhythmia or a family history of sudden cardiac death (Ackerman et al., 2003; Verkerk et al., 2005; Koo et al., 2006; Kapa et al., 2009; Ng et al., 2013; Ghouse et al., 2016; Van Driest et al., 2016); Reported in ClinVar (ClinVar Variant ID# 67419; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32145446, 30821013, 16043162, 22949429, 26746457, 27711072, 19841300, 16487223, 14661677, 23861362, 25351510, 23414114)
Ambry Genetics	RCV002453372	SCV002739640	likely benign	Cardiovascular phenotype	2018-12-26	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.
Fulgent Genetics, Fulgent Genetics	RCV002498334	SCV002804773	likely benign	Short QT syndrome type 1; Long QT syndrome 2	2021-11-08	criteria provided, single submitter	clinical testing
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058144	SCV000089664	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:16487223;PMID:14661677;PMID:16043162;PMID:19841300).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000058144	SCV001550728	likely benign	not provided		no assertion criteria provided	clinical testing	The KCNH2 p.Gly533Ser variant was identified in 1 of 156 proband chromosomes (frequency: 0.0064) from a 57 year old Han Chinese woman with Brugada syndrome; the variant was also found in in 2 of 1000 control chromosomes (frequency: 0.002) from healthy Han Chinese individuals (Verker_2005_PMID:16043162). In a study of 744 apparently healthy individuals, the p.G533S variant was identified in 0.3% of African individuals but was not identified in the Caucasian, Asian or Hispanic individuals (Ackerman_2003_PMID:14661677). Another study identified the variant at a frequency of 0.002 in 265 healthy Chinese individuals (Koo_2006_PMID:16487223). The variant was identified in dbSNP (ID: rs41314354), LOVD 3.0 and ClinVar (classified as likely benign by Invitae, Color and Biesecker Lab/Clinical Genomics Section, National Institutes of Health). The variant was identified in control databases in 74 of 281626 chromosomes at a frequency of 0.0002628 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 57 of 24918 chromosomes (freq: 0.002288), East Asian in 13 of 19928 chromosomes (freq: 0.000652), Latino in 2 of 35424 chromosomes (freq: 0.000056) and European (non-Finnish) in 2 of 128482 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, European (Finnish), Other or South Asian populations. The variant occurs outside of the splicing consensus sequence and two of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a difference in splicing. The p.Gly533 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. Functional data suggest that the p.G533S variant may be a modifer of K+ channel function (Verker_2005_PMID:16043162). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004549485	SCV004777408	likely benign	KCNH2-related disorder	2021-11-10	no assertion criteria provided	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).