Submissions for variant NM_000238.4(KCNH2):c.2717C>T (p.Ser906Leu)

gnomAD frequency: 0.00004  dbSNP: rs199473435

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203863	SCV000260666	pathogenic	Long QT syndrome	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 906 of the KCNH2 protein (p.Ser906Leu). This variant is present in population databases (rs199473435, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of long QT syndrome. It has been shown to exhibit reduced penetrance (PMID: 19716085, 26743238, 31737537, 36269083; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 67429). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects KCNH2 function (PMID: 36269083). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000058154	SCV000539442	likely pathogenic	Congenital long QT syndrome	2024-03-18	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000203863	SCV000748010	uncertain significance	Long QT syndrome	2017-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765943	SCV000897364	uncertain significance	Short QT syndrome type 1; Long QT syndrome 2	2022-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001841718	SCV001354756	likely pathogenic	Cardiac arrhythmia	2023-11-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 906 of the KCNH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a reduction in current density in transfected HEK293 cells (PMID: 36269083). This variant has been reported in 15 unrelated individuals affected with long QT syndrome, idiopathic ventricular fibrillation, or suspected of having long QT syndrome (PMID: 19716085, 26743238, 31737537, 31114860, 32893267, 36269083, ClinVar SCV000260666.6). It has been shown that this variant segregates with disease in multiple families of these individuals (PMID: 36269083). One of the probands carried a second known pathogenic variant in the KCNQ1 gene (PMID: 36269083), who had recurrent syncopal events during exercise and emotional stress. This variant has also been reported in an individual suspected of having Brugada syndrome as well as in a stillbirth case (PMID: 30615648, 36269083). This variant has been identified in 9/124636 chromosomes (6/45878 Non-Finnish European chromosomes, 0.0130%) in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. The elevated allele frequency of this variant in the general population suggests this variant may show reduced penetrance.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470748	SCV002767248	uncertain significance	Long QT syndrome 2	2024-10-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Long QT syndrome 2 (MIM#613688). Gain of function is also a known mechanism associated with Short QT syndrome 1 (MIM#609620) (OMIM, PMID: 10753933; PMID: 21777565). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 20301308). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v4) <0.001 for a dominant condition (121 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in-silico predictions and uninformative conservation. (I) 0600 - Variant is located in an annotated domain or motif (C-terminal; PDB) (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as either a VUS or likely pathogenic in individuals with LQTS, idiopathic ventricular fibrillation, and in a stillbirth case (ClinVar, PMIDs: 36269083, 32893267, 19716085, 26743238, 31737537, 31114860, 30615648). (I) 0906 - Segregation evidence for this variant is inconclusive. This variant segregated with features of LQTS in seven individuals from multiple families. However, five gene positive individuals were unaffected at the time of assessment (PMID: 36269083). (I) 1004 - This variant has moderate functional evidence supporting normal protein function. Automated patch clamp functional studies have shown that this variant results in a 36% reduction in current density, which is comparable to some benign variants. Additionally, this variant has normal channel gating deactivation (personal communication with Victor Chang Victor Chang Cardiac Research Institute, PMID: 36269083). (SB) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Ambry Genetics	RCV003298110	SCV003997349	uncertain significance	Cardiovascular phenotype	2021-04-02	criteria provided, single submitter	clinical testing	The c.2717C>T (p.S906L) alteration is located in exon 12 (coding exon 12) of the KCNH2 gene. This alteration results from a C to T substitution at nucleotide position 2717, causing the serine (S) at amino acid position 906 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058154	SCV000089674	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.
Clinical Genetics, Academic Medical Center	RCV001699029	SCV001917267	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001699029	SCV001932191	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739329	SCV005361319	uncertain significance	KCNH2-related disorder	2024-05-24	no assertion criteria provided	clinical testing	The KCNH2 c.2717C>T variant is predicted to result in the amino acid substitution p.Ser906Leu. This variant has been reported in multiple individuals with long QT syndrome (Table S2, Kapplinger et al. 2009. PubMed ID: 19716085; Supplemental Table, Marschall et al. 2019. PubMed ID: 31737537), idiopathic ventricular fibrillation (Table 4, Blom et al. 2019. PubMed ID: 31114860), unspecified arrhythmogenic disorders (Table S1, Adler et al. 2016. PubMed ID: 26743238; Table S1, Copier et al. 2023. PubMed ID: 36269083), and one case of stillbirth (Table S2, Sahlin et al. 2019. PubMed ID: 30615648). This variant was also found to co-occur with additional variants in genes associated with arrhythmogenic disorders (CACNA1C, PKP2, RYR2, and AKAP9), including an established pathogenic KCNQ1 p.Thr587Met variant (Table S1, Copier et al. 2023. PubMed ID: 36269083). An in vitro experimental study suggests this variant affects the current density and activation gating of the channel protein (Figure 4, Copier et al. 2023. PubMed ID: 36269083). This variant is reported in 0.013% of alleles in individuals of European (non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from uncertain to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/67429/). This variant has been proposed to be associated reduced penetrance with variable clinical presentation (Copier et al. 2023. PubMed ID: 36269083). Although we suspect this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.