Submissions for variant NM_000218.3(KCNQ1):c.1486_1487del (p.Leu496fs)

dbSNP: rs397508090

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520593	SCV000617234	pathogenic	not provided	2022-01-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29511324, 22956155, 24372464, 16414944, 27917693, 28438721)
Color Diagnostics, LLC DBA Color Health	RCV001841632	SCV002052906	pathogenic	Cardiac arrhythmia	2021-04-19	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 11 of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with long QT syndrome (PMID: 16414944, 28438721). This variant has also been reported in homozygous state in one individual affected with autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 28438721). Additionally, it has been reported in compound heterozygosity with KCNQ1 c.683+5G>A (ClinVar variation ID: 53084) in two siblings affected with JLNS (PMID: 27917693). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
New York Genome Center	RCV001838979	SCV002099018	uncertain significance	KCNQ1-related epilepsy	2021-07-02	criteria provided, single submitter	clinical testing	The inherited heterozygous two nucleotide deletion [c.1486_1487del (p.Leu496AlafsTer19)] identified in exon 11 (of 16) of the KCNQ1 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant has been reported in multiple individuals affected with LQTS and JLNS [PMID: 16414944, 27917693, 24372464, 28438721]. It was reported as homozygous and co-segregated with JLNS in two Saudi Arabian families [PMID: 24372464, 28438721]. In both families, individuals homozygous for this variant as well as several heterozygous carriers had LQTS. Additionally, this variant has been reported in compound heterozygosity with the c.683 + 5 G>A variant in a Chinese family affected with JLNS [PMID: 27917693]. Seizures were not reported in any individual in these studies carrying the c.1486_1487del (p.Leu496AlafsTer19) variant. The variant has been reported as Pathogenic in ClinVar database [Variation ID: 52983, phenotypic condition not provided]. The variant is absent from gnomAD(v3) database suggesting it is not a common benign variant in the populations represented in that database. Based on the available evidence, although pathogenic for LQTS and JLNS, the inherited c.1486_1487del (p.Leu496AlafsTer19)] variant is reported as a Variant of Uncertain Significance in a Gene of Unknown Significance for epilepsy phenotype.
Invitae	RCV001852970	SCV002129065	pathogenic	Long QT syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu496Alafs*19) in the KCNQ1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Jervell and Lange-Nielsen syndrome, long QT syndrome, or sudden unexplained death (PMID: 16414944, 24372464, 29511324). This variant is also known as c.1484_1485delCT. ClinVar contains an entry for this variant (Variation ID: 52983). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002390192	SCV002700456	pathogenic	Cardiovascular phenotype	2020-09-23	criteria provided, single submitter	clinical testing	The c.1486_1487delCT pathogenic mutation, located in coding exon 11 of the KCNQ1 gene, results from a deletion of two nucleotides at nucleotide positions 1486 to 1487, causing a translational frameshift with a predicted alternate stop codon (p.L496Afs*19). This mutation has been reported in several long QT syndrome cohorts, including multiple Jervell and Lange-Nielsen homozygous and compound heterozygous probands and affected heterozygous family members (Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Al-Aama JY et al. Clin. Genet., 2015 Dec;87:74-9; Wang C et al. Acta Otolaryngol., 2017 May;137:522-528; Al-Hassnan ZN et al. Heart Rhythm, 2017 08;14:1191-1199). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.