chr11-2588718-G-GA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000218.3(KCNQ1):c.1265dup(p.Phe423ValfsTer40) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K419K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000218.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.1265dup | p.Phe423ValfsTer40 | frameshift_variant | 10/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.1265dup | p.Phe423ValfsTer40 | frameshift_variant | 10/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.884dup | p.Phe296ValfsTer40 | frameshift_variant | 10/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.908dup | p.Phe304ValfsTer40 | frameshift_variant | 10/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.725dup | p.Phe243ValfsTer40 | frameshift_variant | 5/11 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461222Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726896
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jun 08, 2022 | 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. - |
Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 18, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2022 | 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) - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | 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. - |
Ear malformation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 25, 2021 | 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. - |
Jervell and Lange-Nielsen syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PVS1_Strong, PS4_Moderate, PM2, PM3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at