rs397508104

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.1893del(p.Arg632GlufsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000698 in 1,574,920 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. G629G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000070 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: -0.797

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]

KCNQ1 links:

KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

KCNQ1-AS1 links:

Genome browser will be placed here

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. There are 7 pathogenic variants in the truncated region.

PP5

Variant 11-2847858-GC-G is Pathogenic according to our data. Variant chr11-2847858-GC-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2847858-GC-G is described in Lovd as [Pathogenic]. Variant chr11-2847858-GC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1893del	p.Arg632GlufsTer34	frameshift_variant	16/16	ENST00000155840.12
KCNQ1-AS1	NR_130721.1 linkuse as main transcript	n.778-7417del		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1893del	p.Arg632GlufsTer34	frameshift_variant	16/16	1	NM_000218.3	P1	P51787-1
KCNQ1-AS1	ENST00000440887.2 linkuse as main transcript	n.777-7417del		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000703

AC:

AN:

1422680

Hom.:

Cov.:

AF XY:

0.00000994

AC XY:

AN XY:

704064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000501

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000267

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000549

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 06, 2023	This sequence change creates a premature translational stop signal (p.Arg632Glufs*34) 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: 16414944, 22739119). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 53026). 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	Aug 23, 2023	This variant deletes a single nucleotide in the last exon 16 of the KCNQ1 gene, creating a frameshift at codon 632 followed by addition of 33 new amino acids and a stop codon. As a result, this variant alters the cytoplasmic C-terminal region of the KCNQ1 protein. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (PMID: 22739119). This variant has been reported in 2 or more individuals affected with long QT syndrome (PMID: 16414944, 22739119). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Long QT syndrome 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The frameshift variant c.1893del(p.Arg632GlufsTer34) in the KCNQ1 gene has been reported previously in a heterozygous state in individuals affected with Long QT syndrome. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (Egashira et al., 2012; Napolitano et al., 2005). This variant is reported with the allele frequency (0.004%) in the gnomAD Exomes. This variant causes a frameshift starting with codon Arginine 632, changes this amino acid to Glutamic Acid residue, and creates a premature Stop codon at position 34 of the new reading frame. It is submitted to ClinVar as Pathogenic/ Likely pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 29, 2022

Published functional studies using iPSCs and HEK293 cells suggest that that this variant has a dominant negative effect due to a trafficking deficiency (Egashira et al., 2012); Frameshift variant predicted to result in protein truncation, as the last 45 amino acids are replaced with 33 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #53026); This variant is associated with the following publications: (PMID: 19825999, 22739119, 16414944, 27026928, 27110425, 26669661, 30609406, 24657289, 27009425, 23444871, 29976690, 32231684, 34691145) -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jun 29, 2023

This variant deletes a single nucleotide in the last exon 16 of the KCNQ1 gene, creating a frameshift at codon 632 followed by addition of 33 new amino acids and a stop codon. As a result, this variant alters the cytoplasmic C-terminal region of the KCNQ1 protein. An experimental functional study has shown that in transfected cells, the mutant protein carrying this variant has a dominant-negative effect on the channel function due to a trafficking deficiency (PMID: 22739119). This variant has been reported in 2 or more individuals affected with long QT syndrome (PMID: 16414944, 22739119). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over