NM_000218.3:c.914G>A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000218.3(KCNQ1):c.914G>A(p.Trp305*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000218.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.914G>A | p.Trp305* | stop_gained | Exon 6 of 16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
KCNQ1 | ENST00000335475.6 | c.533G>A | p.Trp178* | stop_gained | Exon 6 of 16 | 1 | ENSP00000334497.5 | |||
KCNQ1 | ENST00000496887.7 | c.653G>A | p.Trp218* | stop_gained | Exon 7 of 16 | 5 | ENSP00000434560.2 | |||
KCNQ1 | ENST00000646564.2 | c.478-10456G>A | intron_variant | Intron 2 of 10 | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249180Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135116
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1460482Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4AN XY: 726452
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74356
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Reported in one individual with drug induced Torsades de Pointes (PMID: 24223155); Nonsense 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: 19862833, 25525159, 19716085, 12702160, 19841298, 29876285, 31447099, 23631430, 23995044, 30930557, 24692356, 23124029, 24223155) -
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Long QT syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 6 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual with sudden death and three individuals with long QT syndrome in one family (PMID: 12702160). This variant has been identified in 5/280572 chromosomes 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.Trp305*) 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 (rs120074186, gnomAD 0.008%). This premature translational stop signal has been observed in individuals with LQTS (PMID: 12702160; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53124). For these reasons, this variant has been classified as Pathogenic. -
Cardiac arrhythmia Pathogenic:2
This variant changes 1 nucleotide in exon 6 of the KCNQ1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been shown to segregate with long QT syndrome in three related individuals in a family (PMID: 12702160). This variant has been identified in 5/280572 chromosomes 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. -
Variant summary: KCNQ1 c.914G>A (p.Trp305X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 249180 control chromosomes (gnomAD). c.914G>A has been reported in the literature in multiple individuals affected with Long QT Syndrome (Chen_2003, Schwartz_2009, Cuneo_2013, Lieve_2013) and drug-induced Torsades de Pointes (diTdP) (Behr_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified 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
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Congenital long QT syndrome Pathogenic:1
The p.Trp305X variant in KCNQ1 has been reported in at least 1 individual with long QT syndrome (LQTS) and segregated with disease in at least 3 affected relatives (Chen et al. 2003). It has also been reported by other clinical laboratories in ClinVar (Variation ID 53124) and has been identified in 0.008% (2/24762) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 305, which is predicted to lead to a truncated or absent protein. Loss-of-function variants in KCNQ1 are associated with LQTS (also known as Romano-Ward syndrome) in the heterozygous state and with Jervell and Lange-Nielsen syndrome (JLNS) in the compound heterozygous or homozygous state. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner based upon segregation studies, very low frequency in the general population, and predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PP1_Supporting. -
Cardiovascular phenotype Pathogenic:1
The p.W305* pathogenic mutation (also known as c.914G>A), located in coding exon 6 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 914. This changes the amino acid from a tryptophan to a stop codon within coding exon 6. This alteration has been reported in multiple individuals with long QT syndrome (Chen S. et al. Clin. Genet. 2003;63(4):273-82; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Schwartz PJ et al. Circulation 2009;120(18):1761-7; Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at