Submissions for variant NM_000238.4(KCNH2):c.2941A>G (p.Ser981Gly)

gnomAD frequency: 0.00022  dbSNP: rs76649554

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000058181	SCV000050692	uncertain significance	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000058181	SCV000234203	likely benign	not provided	2020-10-05	criteria provided, single submitter	clinical testing	Observed in two individuals diagnosed with hypertrophic cardiomyopathy (Lopes et al., 2015) and one individual with a history of sudden unexplained death (Sanchez et al., 2016) in the published literature.; Identified in a cohort of ostensibly healthy control individuals (Kappa et al., 2009), a cohort of individuals who underwent exome sequencing who were not selected for cardiomyopathy, arrhythmia, or a family history of sudden cardiac death (Ng et al., 2013), and a cohort of individuals recruited for non-antiarrhythmic drug exposure phenotypes who underwent pharmacogenomic testing (Van Driest et al., 2016); Reported with conflicting interpretations of pathogenicity by other clinical laboratories in ClinVar (ClinVar Variant ID# 67454; 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: 27930701, 22949429, 19841300, 22581653, 23861362, 26746457, 25351510)
Invitae	RCV001086448	SCV000555895	likely benign	Long QT syndrome	2023-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000621297	SCV000736421	likely benign	Cardiovascular phenotype	2021-04-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV001841734	SCV000911333	likely benign	Cardiac arrhythmia	2023-11-13	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001002378	SCV001160293	uncertain significance	not specified	2019-03-02	criteria provided, single submitter	clinical testing	The KCNH2 c.2941A>G; p.Ser981Gly variant (rs76649554; ClinVar Variation ID: 67454) has been previously reported in two individuals included in a cohort of hypertrophic cardiomyopathy (HCM) patients (Lopes 2015). However, this variant has also been identified in several control cohorts (Kapa 2009, Giudicessi 2012, Ng 2013, Van Driest 2016), and is also found in the general population with an overall allele frequency of 0.03% (75/276,264 alleles) in the Genome Aggregation Database. The serine at codon 981 is moderately conserved (Alamut software v2.11) and computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Based on the available information, the clinical significance of this variant is uncertain. References: Giudicessi JR et al. Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome. Circ Cardiovasc Genet. 2012 Oct 1;5(5):519-28. Kapa et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009 Nov 3;120(18):1752-60. Lopes LR et al. Novel genotype-phenotype associations demonstrated by high-throughput sequencing in patients with hypertrophic cardiomyopathy. Heart. 2015 Feb;101(4):294-301. Ng D et al. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet. 2013 Aug;6(4):337-46. Van Driest SL et al. Association of Arrhythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. JAMA. 2016 Jan 5;315(1):47-57.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058181	SCV000089701	not provided	not provided		no assertion provided	literature only	This variant has been reported in the following publications (PMID:19841300).
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000058181	SCV001978292	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000058181	SCV001979433	likely benign	not provided		no assertion criteria provided	clinical testing