11-2445461-A-AT
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000218.3(KCNQ1):c.364dupT(p.Cys122LeufsTer163) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000144 in 1,596,406 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
KCNQ1
NM_000218.3 frameshift
NM_000218.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.34
Genes affected
KCNQ1 (HGNC:6294): (potassium voltage-gated channel subfamily Q member 1) This gene encodes a voltage-gated potassium channel required for repolarization phase of the cardiac action potential. This protein can form heteromultimers with two other potassium channel proteins, KCNE1 and KCNE3. Mutations in this gene are associated with hereditary long QT syndrome 1 (also known as Romano-Ward syndrome), Jervell and Lange-Nielsen syndrome, and familial atrial fibrillation. This gene exhibits tissue-specific imprinting, with preferential expression from the maternal allele in some tissues, and biallelic expression in others. This gene is located in a region of chromosome 11 amongst other imprinted genes that are associated with Beckwith-Wiedemann syndrome (BWS), and itself has been shown to be disrupted by chromosomal rearrangements in patients with BWS. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 11-2445461-A-AT is Pathogenic according to our data. Variant chr11-2445461-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.364dupT | p.Cys122LeufsTer163 | frameshift_variant | Exon 1 of 16 | ENST00000155840.12 | NP_000209.2 | |
KCNQ1 | NM_001406836.1 | c.364dupT | p.Cys122LeufsTer163 | frameshift_variant | Exon 1 of 15 | NP_001393765.1 | ||
KCNQ1 | NM_001406838.1 | c.364dupT | p.Cys122LeufsTer161 | frameshift_variant | Exon 1 of 11 | NP_001393767.1 | ||
KCNQ1 | NM_001406837.1 | c.2dupT | p.Met1IlefsTer13 | frameshift_variant, start_lost | Exon 1 of 17 | NP_001393766.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.364dupT | p.Cys122LeufsTer163 | frameshift_variant | Exon 1 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000345015.4 | n.141dupT | non_coding_transcript_exon_variant | Exon 1 of 3 | 1 | |||||
KCNQ1 | ENST00000496887.7 | c.103dupT | p.Cys35LeufsTer163 | frameshift_variant | Exon 2 of 16 | 5 | ENSP00000434560.2 | |||
KCNQ1 | ENST00000646564.2 | c.364dupT | p.Cys122LeufsTer161 | frameshift_variant | Exon 1 of 11 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000227 AC: 5AN: 219922Hom.: 0 AF XY: 0.0000409 AC XY: 5AN XY: 122282
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GnomAD4 exome AF: 0.0000152 AC: 22AN: 1444266Hom.: 0 Cov.: 31 AF XY: 0.0000278 AC XY: 20AN XY: 718768
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome 1 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Aug 12, 2019 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP4. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 04, 2015 | - - |
KCNQ1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 06, 2024 | The KCNQ1 c.364dupT variant is predicted to result in a frameshift and premature protein termination (p.Cys122Leufs*163). This variant has been reported in the heterozygous state in multiple individuals with long QT syndrome and in the homozygous state in an individual with Jervell and Lange-Nielsen syndrome (described as InsG 2025-2026 K121fs/629* in Tester et al. 2005. PubMed ID: 15840476; Table S1, Schwartz et al. 2021. PubMed ID: 34505893; described as c.365insT in Table S1, Kapplinger et al. 2009. PubMed ID: 19716085; Whiffin et al. 2019. PubMed ID: 30609406; Jacobson et al. 2014. PubMed ID: 24665220). This variant is reported in 0.017% of alleles in individuals of South Asian descent in gnomAD. Frameshift variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 28, 2023 | 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: 34505893, 28606196, 23631430, 19716085, 30609406, 29625023, 26582918, 15840476) - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 07, 2024 | This sequence change creates a premature translational stop signal (p.Cys122Leufs*163) 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 (rs397508109, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome (PMID: 15840476). This variant is also known as Ins G 2025-2026 (K121fs/629*). ClinVar contains an entry for this variant (Variation ID: 200915). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 18, 2019 | The c.364dupT pathogenic mutation, located in coding exon 1 of the KCNQ1 gene, results from a duplication of T at nucleotide position 364, causing a translational frameshift with a predicted alternate stop codon (p.C122Lfs*163). This alteration has been detected in the homozygous state in a child of consanguineous parents who was reported to have Jervell and Lange-Nielsen syndrome. The parents were reported to have normal ECGs (Jacobson D et al. Paediatr Child Health, 2014 Mar;19:123-4). This alteration (also referred to as K121fs/629* and 365insT) has also been detected in long QT syndrome genetic testing cohorts; however, details were limited (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at