rs863224477
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000218.3(KCNQ1):c.585delG(p.Lys196SerfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as 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 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ1 | ENST00000155840.12 | c.585delG | p.Lys196SerfsTer41 | frameshift_variant | Exon 3 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
| KCNQ1 | ENST00000335475.6 | c.204delG | p.Lys69SerfsTer41 | frameshift_variant | Exon 3 of 16 | 1 | ENSP00000334497.5 | |||
| KCNQ1 | ENST00000496887.7 | c.324delG | p.Lys109SerfsTer41 | frameshift_variant | Exon 4 of 16 | 5 | ENSP00000434560.2 | |||
| KCNQ1 | ENST00000646564.2 | c.478-12700delG | intron_variant | Intron 2 of 10 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:4
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The KCNQ1 c.585delG; p.Lys196SerfsTer41 variant (rs397508120) is reported in the literature in multiple individuals affected with long QT syndrome (Kapplinger 2009), as well as a proband with Jervell and Lange-Nielsen syndrome in trans to a second pathogenic variant (Wang 2002). The c.585delG variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Kapplinger et al., Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Wang et al., Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Mol Genet Metab. 2002 Apr;75(4):308-16. -
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: 22629021, 19716085, 18441444, 25649125, 31229680, 31447099, 34411974, 12051962) -
PM2, PM3, PVS1 -
Long QT syndrome Pathogenic:2
This variant deletes 1 nucleotide in exon 3 of the cytoplasmic linker of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals with suspected long QT syndrome (PMID: 19716085, 31229680). It has also been reported in a biallelic individual with severe phenotype (PMID: 12051962). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
This sequence change creates a premature translational stop signal (p.Lys196Serfs*41) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Jervell and Lange-Nielsen Syndrome (PMID: 12051962, 19716085). ClinVar contains an entry for this variant (Variation ID: 53076). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Congenital long QT syndrome Pathogenic:1
The p.Lys196fs variant has been previously reported in the heterozygous state in 4 individuals referred for genetic testing for long QT syndrome (LQTS; Kapplinger 2009) and in the compound heterozygous state in 1 individual with Jervell and Lange-Nielsen syndrome (JLNS; Wang 2002). It has also been reported by other clinical laboratories in ClinVar (Variant ID# 53076) and is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 196 and leads to a premature stop codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Dominant-negative and loss-of-function variants in KCNQ1 cause autosomal dominant LQTS, also known as Romano-Ward syndrome (RWS). In addition, loss of function variants in KCNQ1 also cause autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). In summary, the p.Lys196fs variant meets criteria to be classified as pathogenic for dominant LQTS and recessive JLNS. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3_Supporting -
Cardiovascular phenotype Pathogenic:1
The c.585delG pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 585, causing a translational frameshift with a predicted alternate stop codon (p.K196Sfs*41). This variant was reported in individual(s) with features consistent with long QT syndrome (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). This variant has been identified in the homozygous state and/or in conjunction with other KCNQ1 variant(s) in individual(s) with features consistent with Jervell and Lange-Nielsen syndrome (Wang Z et al. Mol. Genet. Metab., 2002 Apr;75:308-16). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. -
Cardiac arrhythmia Pathogenic:1
This variant deletes 1 nucleotide in exon 3 of the cytoplasmic linker of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals with suspected long QT syndrome (PMID: 19716085, 31229680). It has also been reported in a biallelic individual with severe phenotype (PMID: 12051962). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at