rs397508103
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000218.3(KCNQ1):c.1892_1911del(p.Pro631HisfsTer14) variant causes a frameshift change involving the alteration of a non-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 frameshift
NM_000218.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.68
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 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0689 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-2847862-CCCCAGAGAGGGCGGGGCCCA-C is Pathogenic according to our data. Variant chr11-2847862-CCCCAGAGAGGGCGGGGCCCA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2847862-CCCCAGAGAGGGCGGGGCCCA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| KCNQ1 | NM_000218.3 | c.1892_1911del | p.Pro631HisfsTer14 | frameshift_variant | 16/16 | ENST00000155840.12 | NP_000209.2 | |
| KCNQ1-AS1 | NR_130721.1 | n.778-7440_778-7421del | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| KCNQ1 | ENST00000155840.12 | c.1892_1911del | p.Pro631HisfsTer14 | frameshift_variant | 16/16 | 1 | NM_000218.3 | ENSP00000155840 | P1 | |
| KCNQ1-AS1 | ENST00000440887.2 | n.777-7440_777-7421del | intron_variant, non_coding_transcript_variant | 5 |
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:8Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Long QT syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 22, 2023 | This sequence change creates a premature translational stop signal (p.Pro631Hisfs*14) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 46 amino acid(s) of the KCNQ1 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Jervell and Lange-Nielsen syndrome (PMID: 10024302). This variant is also known as 1892del20. ClinVar contains an entry for this variant (Variation ID: 53025). This variant disrupts a region of the KCNQ1 protein in which other variant(s) (p.Arg632Glufs*34, p.Arg632Lysfs*20) have been determined to be pathogenic (PMID: 16414944, 22739119; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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 | Apr 10, 2023 | This variant deletes 20 nucleotides in exon 16 of the KCNQ1 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few unrelated individuals affected with long QT syndrome (PMID: 26669661, 27379800, 32893267). This variant has also been observed in compound heterozygous state in two unrelated individuals, one affected with Jervell and Lange-Nielsen syndrome (PMID: 10024302) and the other affected with early-onset sudden cardiac arrest, ventricular fibrillation, congenital deafness, and with a family history of long QT syndrome (communication with an external laboratory; ClinVar SCV002719171.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants occurring downstream of this variant are known to cause long QT syndrome (ClinVar). One of these variants, p.Arg632Glnfs*20 (ClinVar variation ID 53027), has been shown to cause protein trafficking defect due to endoplasmic reticulum (ER) retention signal introduced by the frameshift. A similar ER retention signal is also present in the variant p.Pro631Hisfs*14. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
not provided Pathogenic:1Other:1
| not provided, no classification provided | clinical testing | GeneDx | - | The c.1892_1911del pathogenic variant in the KCNQ1 gene has been reported in one family with Jervell Lange-Nielsen syndrome (JLNS) (Neyroud et al., 1999). Neyroud et al. reported c.1892_1911del (denoted 1892del20 due to alternate nomenclature) in one family where this variant was paternally inherited; no second variant was identified in the proband. This variant causes a shift in reading frame starting at codon Proline 631, changing it to a Histidine, and creating a premature stop codon at position 14 of the new reading frame, denoted p.Pro631HisfsX14. This 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 association with LQTS and JLNS. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | KCNQ1: PM2, PS4:Moderate, PVS1:Moderate - |
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
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 12, 2021 | - - |
Jervell and Lange-Nielsen syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 19, 1999 | - - |
KCNQ1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 04, 2023 | The KCNQ1 c.1892_1911del20 variant is predicted to result in a frameshift and premature protein termination (p.Pro631Hisfs*14). This variant was reported in multiple individuals with long QT syndrome (Table S1, Itoh et al. 2015. PubMed ID: 26669661; Samol et al. 2016. PubMed ID: 27379800; Table S4, Walsh et al. 2021. PubMed ID: 32893267). This variant was also reported in an individual with Jervell and Lange-Nielsen syndrome; however, a second plausible causative variant was not identified (described as 1892del20, Neyroud et al. 1999. PubMed ID: 10024302). This variant has not been reported in a large population database, indicating this variant is rare. This variant is located in the terminal exon and nearby frameshift variants have been documented in individuals with long QT syndrome (Napolitano et al. 2005. PubMed ID: 16414944). Taken together, this variant is interpreted as pathogenic. - |
Cardiovascular phenotype Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2018 | The c.1892_1911del20 variant, located in coding exon 16 of the KCNQ1 gene, results from a deletion of 20 nucleotides at nucleotide positions 1892 to 1911, causing a translational frameshift with a predicted alternate stop codon (p.P631Hfs*14). This frameshift occurs at the 3' terminus of KCNQ1, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 46 amino acids of the protein. However, this alteration has been previously reported in long QT syndrome cohorts (Itoh H et al. Eur. J. Hum. Genet., 2016 08;24:1160-6; Samol A et al. PLoS ONE, 2016 Jul;11:e0158085). This deletion allele has also been detected in the heterozygous state in a patient with autosomal recessive Jervell and Lange-Nielsen syndrome, though a second KCNQ1 alteration was not identified (Neyroud N et al. Circ. Res., 1999 Feb;84:290-7). In addition, there is a putative endoplasmic reticulum (ER) retention signal located in the 3' terminus of this alteration that is not present in wild-type KCNQ1; the presence of similar ER retention signals in another frameshift alteration (p.R632Qfs*20) has been shown to result in a trafficking defect (Sato A et al. J. Biol. Chem., 2009 Dec;284:35122-33; Ambry Internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Cardiac arrhythmia Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 26, 2023 | This variant deletes 20 nucleotides in exon 16 of the KCNQ1 gene, creating a frameshift in the last exon. The mutant transcript is expected to escape nonsense-mediated decay and be expressed as a protein product containing altered C-terminal sequence. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a few unrelated individuals affected with long QT syndrome (PMID: 26669661, 27379800, 32893267). This variant has also been observed in compound heterozygous state in two unrelated individuals, one affected with Jervell and Lange-Nielsen syndrome (PMID: 10024302) and the other affected with early-onset sudden cardiac arrest, ventricular fibrillation, congenital deafness, and with a family history of long QT syndrome (communication with an external laboratory; ClinVar SCV002719171.1). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Truncation variants occurring downstream of this variant are known to cause long QT syndrome (ClinVar). One of these variants, p.Arg632GlnfsTer20 (ClinVar variation ID 53027), has been shown to cause a protein trafficking defect due to endoplasmic reticulum (ER) retention signal introduced by the frameshift. A similar ER retention signal is also present in the variant p.Pro631HisfsTer14. Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at