rs397508110
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000218.3(KCNQ1):c.451_452del(p.Leu151GlyfsTer133) variant causes a frameshift change. 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
Genomes: not found (cov: 34)
Consequence
KCNQ1
NM_000218.3 frameshift
NM_000218.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.46
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 11-2527991-CCT-C is Pathogenic according to our data. Variant chr11-2527991-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 53045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2527991-CCT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.451_452del | p.Leu151GlyfsTer133 | frameshift_variant | 2/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.451_452del | p.Leu151GlyfsTer133 | frameshift_variant | 2/16 | 1 | NM_000218.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Jervell and Lange-Nielsen syndrome 1 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 16, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 11, 2019 | The c.451_452delCT pathogenic variant in the KCNQ1 gene has previously been reported as a homozygous variant in two siblings with Jervell-Lange Nielsen syndrome (JLNS), who each exhibited markedly prolonged QT intervals and congenital deafness (Chen et al., 1999). This case report also noted the heterozygous parents had borderline QT intervals and this variant was not detected in 100 healthy control individuals (Chen et al., 1999). The c.451_452delCT variant has subsequently been observed in one individual with autosomal dominant LQTS, and was absent in >2,600 alleles from control individuals (Kapplinger et al., 2009). This variant causes a shift in reading frame starting at codon leucine 151, changing it to a glycine, and creating a premature stop codon at position 133 of the new reading frame, denoted p.Leu151GlyfsX133. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Other frameshift variants in the KCNQ1 gene have been reported in Human Gene Mutation Database in association with KCNQ1-related disorders (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.451_452delCT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Leu151Glyfs*133) 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 autosomal recessive Jervell and Lange-Nielsen syndrome (PMID: 10077519). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53045). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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