rs397508127
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM4_SupportingPP5_Very_Strong
The NM_000218.3(KCNQ1):c.828_830del(p.Ser277del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
KCNQ1
NM_000218.3 inframe_deletion
NM_000218.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.41
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 11 ACMG points.
PM1
?
In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000218.3
PM4
?
Nonframeshift variant in NON repetitive region in NM_000218.3. Strenght limited to Supporting due to length of the change: 1aa.
PP5
?
Variant 11-2572889-TCTC-T is Pathogenic according to our data. Variant chr11-2572889-TCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 53114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572889-TCTC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNQ1 | NM_000218.3 | c.828_830del | p.Ser277del | inframe_deletion | 6/16 | ENST00000155840.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNQ1 | ENST00000155840.12 | c.828_830del | p.Ser277del | inframe_deletion | 6/16 | 1 | NM_000218.3 | P1 | |
KCNQ1 | ENST00000335475.6 | c.447_449del | p.Ser150del | inframe_deletion | 6/16 | 1 | |||
KCNQ1 | ENST00000496887.7 | c.567_569del | p.Ser190del | inframe_deletion | 7/16 | 5 | |||
KCNQ1 | ENST00000646564.2 | c.478-10542_478-10540del | intron_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2020 | Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on protein structure/function; Published functional studies demonstrate this variant results in reduced potassium channel activity (reported as S276del due to alternate nomenclature; Gouas et al., 2004); This variant is associated with the following publications: (PMID: 20890437, 22539601, 15194462, 27485560, 15176425, 16414944, 32048431, 31737537) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Long QT syndrome 1 Pathogenic:2
Pathogenic, no assertion criteria provided | research | Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital | Jan 01, 2013 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Feb 15, 2018 | - - |
not specified Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Nov 06, 2015 | - - |
Long QT syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 27, 2023 | For these reasons, this variant has been classified as Pathogenic. This variant, c.828_830del, results in the deletion of 1 amino acid(s) of the KCNQ1 protein (p.Ser277del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with Jervell and Lange-Nielsen syndrome and/or Long QT syndrome (PMID: 20890437, 22539601; Invitae). This variant is also known as p.Ser276del. ClinVar contains an entry for this variant (Variation ID: 53114). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects KCNQ1 function (PMID: 15194462). This variant disrupts the p.Ser277 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12442276, 16414944, 19716085, 21241800, 21895724, 23130128). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. - |
Computational scores
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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