Submissions for variant NM_000218.3(KCNQ1):c.1265dup (p.Phe423fs)

dbSNP: rs397508083

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523754	SCV000617233	likely pathogenic	not provided	2022-05-23	criteria provided, single submitter	clinical testing	Reported in association with Long QT syndrome (Lupoglazoff et al., 2004; Tester et al., 2005); Not observed at 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; This variant is associated with the following publications: (PMID: 19862833, 15840476, 26669661, 14998624)
Kariminejad - Najmabadi Pathology & Genetics Center	RCV001814030	SCV001755330	pathogenic	Ear malformation	2021-07-10	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV003227628	SCV002578957	pathogenic	Long QT syndrome 1	2022-04-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002444507	SCV002679960	pathogenic	Cardiovascular phenotype	2021-02-25	criteria provided, single submitter	clinical testing	The c.1265dupA pathogenic mutation, located in coding exon 10 of the KCNQ1 gene, results from a duplication of A at nucleotide position 1265, causing a translational frameshift with a predicted alternate stop codon (p.F423Vfs*40). This mutation (also referred to as g.1258 ins A and ins A 1265–1266) has been reported in association with long QT syndrome (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Lupoglazoff JM et al. J Am Coll Cardiol, 2004 Mar;43:826-30). 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	RCV002477153	SCV002783626	likely pathogenic	Atrial fibrillation, familial, 3; Beckwith-Wiedemann syndrome; Long QT syndrome 1; Jervell and Lange-Nielsen syndrome 1; Short QT syndrome type 2	2021-09-18	criteria provided, single submitter	clinical testing
New York Genome Center	RCV003227628	SCV003925157	pathogenic	Long QT syndrome 1	2022-06-08	criteria provided, single submitter	clinical testing	The one nucleotide duplication [c.1265dup p.(Phe423ValfsTer40)] identified in exon 10 (of 16) of KCNQ1 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. This variant as well as an adjacent one nucleotide duplication with the same predicted effect on protein [c.1266dupG p.(Phe423ValfsTer40)] have been reported in individuals affected with long QTsyndrome [PMID:15840476, 24912595]. The c.1265dup variant identified here has been reported in ClinVar database as Pathogenic/Likely Pathogenic[Variation ID: 52974], and is absent from population databases (gnomADv2, gnomADv3, TOPMed Freeze 8) suggesting it is not a common benign variant inpopulations represented in those databases. Based on the available evidence, the c.1265dup p.(Phe423ValfsTer40) variant identified in the KCNQ1 gene is reported as Pathogenic.
Dept of Medical Biology, Uskudar University	RCV003318348	SCV004022031	pathogenic	Jervell and Lange-Nielsen syndrome	2024-01-08	criteria provided, single submitter	research	Criteria: PVS1_Strong, PS4_Moderate, PM2, PM3
Labcorp Genetics (formerly Invitae), Labcorp	RCV003531942	SCV004294079	pathogenic	Long QT syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe423Valfs*40) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Long QT syndrome (PMID: 15840476, 34860437). This variant is also known as ins A 1265–1266, K422fs/39*. ClinVar contains an entry for this variant (Variation ID: 52974). For these reasons, this variant has been classified as Pathogenic.