Submissions for variant NM_000219.6(KCNE1):c.-5C>A

gnomAD frequency: 0.00005  dbSNP: rs191334763

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000607041	SCV000711388	uncertain significance	not specified	2017-09-14	criteria provided, single submitter	clinical testing	The c.-5C>A variant in KCNE1 has not been previously reported in individuals wit h arrhythmia or hearing loss, but has been identified in 0.1% (19/18862) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.bro adinstitute.org; dbSNP rs191334763).This variant is located in the 5' UTR and is part of the translation initiation (Kozak) sequence, but its effect on translat ion is unknown. In summary, the clinical significance of the c.-5C>A variant is uncertain.
Ambry Genetics	RCV000617837	SCV000736021	likely benign	Cardiovascular phenotype	2021-05-25	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.
Illumina Laboratory Services, Illumina	RCV001139932	SCV001300132	uncertain significance	Long QT syndrome 5	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001139933	SCV001300133	uncertain significance	Jervell and Lange-Nielsen syndrome 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001553447	SCV001774317	likely benign	not provided	2020-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000607041	SCV003934366	benign	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: KCNE1 c.-5C>A is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 6.8e-05 in 250842 control chromosomes, predominantly at a frequency of 0.00093 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 446.4 fold of the estimated maximal estimated allele frequency for a pathogenic variant in KCNE1 causing Long QT Syndrome phenotype (2.1e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.-5C>A has been reported in the literature in at least one individual affected with atrioventricular nodal reentry tachycardia, however without strong evidence for causality (e.g., Luo_2020). This report therefore does not provide unequivocal conclusions about association of the variant with Long QT Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication was ascertained in the context of this evaluation (PMID: 32508047). Four ClinVar submitters (evaluation after 2014) have cited with conflicting assessments: two submitters classified the variant as likely benign, and two submitters classified the variant as VUS. Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV001553447	SCV005410134	uncertain significance	not provided	2024-06-19	criteria provided, single submitter	clinical testing