rs530612385
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000218.3(KCNQ1):c.564G>A(p.Trp188Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,076 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
KCNQ1
NM_000218.3 stop_gained
NM_000218.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 5.23
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 11-2570714-G-A is Pathogenic according to our data. Variant chr11-2570714-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 263738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570714-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.564G>A | p.Trp188Ter | stop_gained | 3/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.564G>A | p.Trp188Ter | stop_gained | 3/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.183G>A | p.Trp61Ter | stop_gained | 3/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.303G>A | p.Trp101Ter | stop_gained | 4/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-12721G>A | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460076Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726454
GnomAD4 exome
AF:
AC:
2
AN:
1460076
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
726454
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 01, 2023 | This sequence change creates a premature translational stop signal (p.Trp188*) 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 individual(s) with clinical features of long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 263738). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 04, 2024 | The c.564G>A (p.Trp188*) variant in the KCNQ1 gene creates a premature translational stop codon in the KCNQ1 gene. It is predicted to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, PMID: 26318259). This variant is absent in the general population database (gnomAD). ClinVar contains an entry for this variant (Variation ID: 263738). Based on the available evidence the c.564G>A (p.Trp188*) variant in the KCNQ1 gene is classified as likely pathogenic. - |
Long QT syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) | Apr 01, 2023 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2022 | Reported in an individual with Long QT syndrome in published literature (Kapplinger et al., 2009); clinical information is limited; 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: 19716085) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 23, 2015 | The p.W188* pathogenic mutation (also known as c.564G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 564. This changes the amino acid at codon 188 from a tryptophan to a stop codon. In a study of long QT syndrome clinical genetic testing, this nonsense pathogenic mutation was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). In addition, nonsense mutations in the KCNQ1 gene have been described in multiple individuals with long QT syndrome and arrhythmias, demonstrating truncation mutations are pathogenic for disease. In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
0.91, 0.90
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at