NM_000218.3:c.364dupT
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
Consequence
NM_000218.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
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
GnomAD3 exomes AF: 0.0000227 AC: 5AN: 219922Hom.: 0 AF XY: 0.0000409 AC XY: 5AN XY: 122282
GnomAD4 exome AF: 0.0000152 AC: 22AN: 1444266Hom.: 0 Cov.: 31 AF XY: 0.0000278 AC XY: 20AN XY: 718768
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152140Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74326
ClinVar
Submissions by phenotype
Long QT syndrome 1 Pathogenic:3
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP4. -
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KCNQ1-related disorder Pathogenic:1
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
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
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
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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at