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rs794728557

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_ModeratePM2PP3PP5_Very_Strong

The NM_000218.3(KCNQ1):c.919_921+9del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G306G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 splice_donor, splice_donor_5th_base, coding_sequence, intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.36
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 13 ACMG points.

PVS1
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.054945055 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant 11-2572981-GGGGTGGTAAGTC-G is Pathogenic according to our data. Variant chr11-2572981-GGGGTGGTAAGTC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572981-GGGGTGGTAAGTC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KCNQ1NM_000218.3 linkuse as main transcriptc.919_921+9del splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant 6/16 ENST00000155840.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KCNQ1ENST00000155840.12 linkuse as main transcriptc.919_921+9del splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant 6/161 NM_000218.3 P1P51787-1
KCNQ1ENST00000335475.6 linkuse as main transcriptc.538_540+9del splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant 6/161 P51787-2
KCNQ1ENST00000496887.7 linkuse as main transcriptc.658_660+9del splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant 7/165
KCNQ1ENST00000646564.2 linkuse as main transcriptc.478-10451_478-10440del intron_variant

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460654
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
726516
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMolecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart InstituteMay 30, 2016- -
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxAug 15, 2016The c.919_921+9del12 variant in the KCNQ1 gene has not been reported to our knowledge. The c.919_921+9del12 variant results in a 12-bp deletion of the exonic GTG nucleotides and intronic gtaagtcgg nucleotides spanning an exon-intron boundary. This variant is expected to destroy the splice donor site of intron 6. The c.919_921+9del12 variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. While the c.919_921+9del12 variant has not been published, it is expected to be pathogenic, as loss of function variants in this gene are strongly associated with this phenotype. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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: rs794728557; hg19: chr11-2594211; API