rs397508126
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PM4_SupportingPP5_Very_Strong
The NM_000218.3(KCNQ1):c.824_826delTCT(p.Phe275del) variant causes a disruptive inframe deletion 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ1
NM_000218.3 disruptive_inframe_deletion
NM_000218.3 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.52
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
In a transmembrane_region Helical; Name=Segment S5 (size 20) in uniprot entity KCNQ1_HUMAN there are 30 pathogenic changes around while only 0 benign (100%) in NM_000218.3
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000218.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
Variant 11-2572885-ATCT-A is Pathogenic according to our data. Variant chr11-2572885-ATCT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572885-ATCT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ1 | ENST00000155840.12 | c.824_826delTCT | p.Phe275del | disruptive_inframe_deletion | 6/16 | 1 | NM_000218.3 | ENSP00000155840.2 | ||
| KCNQ1 | ENST00000335475.6 | c.443_445delTCT | p.Phe148del | disruptive_inframe_deletion | 6/16 | 1 | ENSP00000334497.5 | |||
| KCNQ1 | ENST00000496887.7 | c.563_565delTCT | p.Phe188del | disruptive_inframe_deletion | 7/16 | 5 | ENSP00000434560.2 | |||
| KCNQ1 | ENST00000646564.2 | c.478-10546_478-10544delTCT | intron_variant | ENSP00000495806.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
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 1 Pathogenic:2
| Pathogenic, no assertion criteria provided | research | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jan 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Dec 15, 2017 | - - |
Long QT syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 17, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this variant affects KCNQ1 function (PMID: 17655673). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 53112). This variant is also known as ΔF275. This variant has been observed in individuals with clinical features of KCNQ1-related conditions and/or long QT syndrome (PMID: 17655673, 27485560, 31737537; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.824_826del, results in the deletion of 1 amino acid(s) of the KCNQ1 protein (p.Phe275del), but otherwise preserves the integrity of the reading frame. - |
| Pathogenic, criteria provided, single submitter | research | Dept of Medical Biology, Uskudar University | Jan 08, 2024 | Criteria: PS4_Strong, PS3_Moderate, PM2, PM4 - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2019 | Not observed in large population cohorts (Lek et al., 2016); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53112; Landrum et al., 2016); In-frame deletion of one amino acids in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Published functional studies demonstrate a loss-of-function when expressed in isolation and suggest dominant negative effect when co-expressed with the wildtype protein (Aizawa et al., 2007); This variant is associated with the following publications: (PMID: 31737537, 17655673, 27485560) - |
Computational scores
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Calibrated prediction
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Prediction
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at