Submissions for variant NM_000218.3(KCNQ1):c.-5T>C

gnomAD frequency: 0.00267  dbSNP: rs532941548

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000155746	SCV000169951	benign	not specified	2012-03-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155746	SCV000205456	likely benign	not specified	2018-02-28	criteria provided, single submitter	clinical testing	c.-5T>C in the 5'UTR of KCNQ1: This variant is classified as likely benign becau se it has been identified in 0.34% (47/13662) of European chromosomes by the Gen ome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs532 941548). ACMG/AMP Criteria applied: BS1.
Ambry Genetics	RCV000242002	SCV000319135	likely benign	Cardiovascular phenotype	2018-05-21	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.
Eurofins Ntd Llc (ga)	RCV000725213	SCV000335034	uncertain significance	not provided	2015-09-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000389967	SCV000370195	likely benign	Long QT syndrome 1	2018-08-15	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000310463	SCV000370196	uncertain significance	Atrial fibrillation, familial, 3	2018-08-15	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000364999	SCV000370197	likely benign	Congenital long QT syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000270523	SCV000370198	uncertain significance	Short QT syndrome type 2	2018-08-16	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000307327	SCV000370199	uncertain significance	Jervell and Lange-Nielsen syndrome 1	2018-08-15	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Athena Diagnostics Inc	RCV000725213	SCV001144353	uncertain significance	not provided	2018-11-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000725213	SCV001248097	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	KCNQ1: BP4
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155746	SCV001339051	benign	not specified	2022-01-31	criteria provided, single submitter	clinical testing	Variant summary: KCNQ1 c.-5T>C is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0027 in 146374 control chromosomes in the gnomAD database (v3.1 genomes dataset), including 1 homozygote. The observed variant frequency is approximately 26-fold higher than the estimated maximal expected allele frequency for a pathogenic variant in KCNQ1 causing Arrhythmia phenotype (0.0001), strongly suggesting that the variant is benign. c.-5T>C has been reported in the literature in individuals affected with or being tested for LQTS, without strong evidence for causality (Jongbloed_2002, Stattin_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign (n=4) or VUS (n=2). Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV000155746	SCV001923127	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000725213	SCV001931844	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000725213	SCV001957121	likely benign	not provided		no assertion criteria provided	clinical testing