GeneBe

11-2588718-GAAAA-GAAAAA

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1265dupA​(p.Phe423ValfsTer40) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000274 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.91
Variant links:
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 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 11-2588718-G-GA is Pathogenic according to our data. Variant chr11-2588718-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KCNQ1NM_000218.3 linkc.1265dupA p.Phe423ValfsTer40 frameshift_variant Exon 10 of 16 ENST00000155840.12 NP_000209.2 P51787-1Q96AI9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KCNQ1ENST00000155840.12 linkc.1265dupA p.Phe423ValfsTer40 frameshift_variant Exon 10 of 16 1 NM_000218.3 ENSP00000155840.2 P51787-1
KCNQ1ENST00000335475.6 linkc.884dupA p.Phe296ValfsTer40 frameshift_variant Exon 10 of 16 1 ENSP00000334497.5 P51787-2
KCNQ1ENST00000496887.7 linkc.908dupA p.Phe304ValfsTer40 frameshift_variant Exon 10 of 16 5 ENSP00000434560.2 E9PPZ0
KCNQ1ENST00000646564.2 linkc.725dupA p.Phe243ValfsTer40 frameshift_variant Exon 5 of 11 ENSP00000495806.2 A0A2R8YEQ9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461222
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726896
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000188
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Long QT syndrome 1 Pathogenic:3
Apr 25, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 08, 2022
New York Genome Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The one nucleotide duplication [c.1265dup p.(Phe423ValfsTer40)] identified in exon 10 (of 16) of KCNQ1 alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant as well as an adjacent one nucleotide duplication with the same predicted effect on protein [c.1266dupG p.(Phe423ValfsTer40)] have been reported in individuals affected with long QTsyndrome [PMID:15840476, 24912595]. The c.1265dup variant identified here has been reported in ClinVar database as Pathogenic/Likely Pathogenic[Variation ID: 52974], and is absent from population databases (gnomADv2, gnomADv3, TOPMed Freeze 8) suggesting it is not a common benign variant inpopulations represented in those databases. Based on the available evidence, the c.1265dup p.(Phe423ValfsTer40) variant identified in the KCNQ1 gene is reported as Pathogenic. -

Mar 15, 2024
3billion
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000052974 /PMID: 15840476). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

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
Sep 18, 2021
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
May 23, 2022
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Reported in association with Long QT syndrome (Lupoglazoff et al., 2004; Tester et al., 2005); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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; This variant is associated with the following publications: (PMID: 19862833, 15840476, 26669661, 14998624) -

Long QT syndrome Pathogenic:1
Aug 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Phe423Valfs*40) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Long QT syndrome (PMID: 15840476, 34860437). This variant is also known as ins A 1265–1266, K422fs/39*. ClinVar contains an entry for this variant (Variation ID: 52974). For these reasons, this variant has been classified as Pathogenic. -

Ear malformation Pathogenic:1
Jul 10, 2021
Kariminejad - Najmabadi Pathology & Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Cardiovascular phenotype Pathogenic:1
Feb 25, 2021
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1265dupA pathogenic mutation, located in coding exon 10 of the KCNQ1 gene, results from a duplication of A at nucleotide position 1265, causing a translational frameshift with a predicted alternate stop codon (p.F423Vfs*40). This mutation (also referred to as g.1258 ins A and ins A 1265&ndash;1266) has been reported in association with long QT syndrome (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Lupoglazoff JM et al. J Am Coll Cardiol, 2004 Mar;43:826-30). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Jervell and Lange-Nielsen syndrome Pathogenic:1
Jan 08, 2024
Dept of Medical Biology, Uskudar University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

Criteria: PVS1_Strong, PS4_Moderate, PM2, PM3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs397508083; hg19: chr11-2609948; API