Submissions for variant NM_172201.2(KCNE2):c.347C>T (p.Ala116Val)

gnomAD frequency: 0.00003  dbSNP: rs199473367

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000222131	SCV000279568	likely pathogenic	not provided	2016-08-12	criteria provided, single submitter	clinical testing	The A116V likely pathogenic variant in the KCNE2 gene has been reported in one individual with drug-induced LQTS, and was absent in >2,000 control alleles (Sesti et al., 2000). Additionally, the A116V variant has previously been identified in one other unrelated individual referred for cardiac genetic testing at GeneDx. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the A116V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, it occurs at a position that is conserved across species. Furthermore, functional studies show that A116V results in diminished potassium current in CHO cells co-expressing wild type KCNH2 channel, which may result in increased susceptibility to drug-induced QT prolongation (Sesti et al., 2000). However, the effect of this variant on baseline QT interval and constitutional susceptibility to arrhythmia is unclear.Therefore, this variant is likely pathogenic. In order to definitively determine its clinical significance, additional data is required.
Neuberg Centre For Genomic Medicine, NCGM	RCV001823107	SCV002073142	likely pathogenic	Long QT syndrome 6		criteria provided, single submitter	clinical testing	The missense variant p.A116V in KCNE2 (NM_172201.2) has been reported previously in a patient who had drug induced prolongation of QT interval and functional studies in CHO cells depicted a damaging impact (Sesti F et al, 2000). It has been submitted to ClinVar as Likely Pathogenic/Uncertain Significance. The missense variant c.347C>T (p.A116V) in KCNE2 (NM_172201.2) is observed in 1/16222 (0.0062%) alleles from individuals of African background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools predict the variant to be damaging. For these reasons, this variant has been classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001823107	SCV002119832	uncertain significance	Long QT syndrome 6	2022-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 116 of the KCNE2 protein (p.Ala116Val). This variant is present in population databases (rs199473367, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 10984545). ClinVar contains an entry for this variant (Variation ID: 67620). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects KCNE2 function (PMID: 10984545). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001823107	SCV002768163	uncertain significance	Long QT syndrome 6	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are proposed mechanisms of disease in this gene and are associated with long QT syndrome 6 (MIM#613693) and familial atrial fibrillation (MIM#611493), respectively. However, this should be interpreted with caution as the gene-disease association for KCNE2 is currently unclear (PMIDs: 22166675, 26123744, 24796621, 28794082, 15368194). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to valine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (12 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated cytoplasmic region (UniProt). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous reports of pathogenicity for this variant are conflicting. This variant has been identified in an individual with drug-induced LQTS who had a history of cardiac arrest associated with substance abuse (PMID: 10984545). This variant has been identified by the GeneDx laboratory in a individual with a history of syncope and in another individual in which no phenotypic information was provided. It was classified as a VUS (GeneDx personal communication). Additionally, this variant has been identified in two individuals undergoing preconception carrier screening who did not have a family history of an inheritable genetic condition (PMID: 31589614). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - Moderate functional evidence supporting abnormal protein function. Patch clamp analysis in CHO cells has shown that this variant causes a reduction in potassium current density (PMID: 10984545). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058374	SCV000089894	not provided	Acquired long QT syndrome		no assertion provided	literature only	This variant has been reported as associated with acquired long QT syndrome, drug induced in the following publications (PMID:10984545;PMID:14760488). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.