Submissions for variant NM_000218.3(KCNQ1):c.796del (p.Leu266fs)

dbSNP: rs397508125

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182270	SCV000234573	pathogenic	not provided	2022-01-04	criteria provided, single submitter	clinical testing	Reported in patients with LQTS in the published literature (Napolitano et al., 2005; Kapplinger et al., 2009); Not observed at a significant frequency in large population cohorts (gnomAD); 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; Reported in ClinVar as a pathogenic variant (ClinVar Variant ID# 53107); This variant is associated with the following publications: (PMID: 19716085, 22956155, 34319147, 16414944)
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000735818	SCV000863952	pathogenic	Long QT syndrome 1	2018-12-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001038095	SCV001201542	pathogenic	Long QT syndrome	2024-01-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu266Cysfs*23) 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 present in population databases (rs397508125, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with long QT syndrome or referred for long QT syndrome testing (PMID: 16414944, 19716085). ClinVar contains an entry for this variant (Variation ID: 53107). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002415499	SCV002676477	pathogenic	Cardiovascular phenotype	2023-02-13	criteria provided, single submitter	clinical testing	The c.796delC pathogenic mutation, located in coding exon 6 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 796, causing a translational frameshift with a predicted alternate stop codon (p.L266Cfs*23). This alteration has been detected in individuals referred for long QT syndrome genetic testing (Napolitano C et al. JAMA, 2005 Dec;294:2975-80; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Fulgent Genetics, Fulgent Genetics	RCV002504940	SCV002813002	pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-09-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001038095	SCV004825827	pathogenic	Long QT syndrome	2023-08-16	criteria provided, single submitter	clinical testing	This variant is predicted to result in loss of protein function through nonsense-mediated or protein truncation. Loss of function is an established mechanism of disease. This variant has been reported in multiple individuals with long QT syndrome or referred for long QT syndrome genetic testing (PMID: 19716085, 23631430, 22956155, 34319147, 16414944). It is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).