rs397508109

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000218.3(KCNQ1):c.364dup(p.Cys122LeufsTer163) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000144 in 1,596,406 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. K121K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.34

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 11-2445461-A-AT is Pathogenic according to our data. Variant chr11-2445461-A-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 200915.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
KCNQ1	NM_000218.3 linkuse as main transcript	c.364dup	p.Cys122LeufsTer163	frameshift_variant	1/16	ENST00000155840.12
KCNQ1	NM_001406836.1 linkuse as main transcript	c.364dup	p.Cys122LeufsTer163	frameshift_variant	1/15
KCNQ1	NM_001406838.1 linkuse as main transcript	c.364dup	p.Cys122LeufsTer161	frameshift_variant	1/11
KCNQ1	NM_001406837.1 linkuse as main transcript	c.2dup	p.Met1?	frameshift_variant, start_lost	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.364dup	p.Cys122LeufsTer163	frameshift_variant	1/16	1	NM_000218.3	P1	P51787-1
KCNQ1	ENST00000345015.4 linkuse as main transcript	n.141dup		non_coding_transcript_exon_variant	1/3	1
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.103dup	p.Cys35LeufsTer163	frameshift_variant	2/16	5
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.364dup	p.Cys122LeufsTer161	frameshift_variant	1/11

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

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:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000227

AC:

AN:

219922

Hom.:

AF XY:

0.0000409

AC XY:

AN XY:

122282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000168

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1444266

Hom.:

Cov.:

AF XY:

0.0000278

AC XY:

AN XY:

718768

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:

0.000256

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome 1

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Arcensus	Feb 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 12, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 04, 2015	- -

KCNQ1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2023

The KCNQ1 c.364dupT variant is predicted to result in a frameshift and premature protein termination (p.Cys122Leufs*163). This variant has been reported in multiple individuals with long QT syndrome in both the heterozygous and homozygous state (described as InsG 2025-2026 K121fs/629* in Tester et al. 2005. PubMed ID: 15840476; Schwartz et al. 2021. PubMed ID: 34505893; described as c.365insT in Kapplinger et al. 2009. PubMed ID: 19716085; Whiffin et al. 2019. PubMed ID: 30609406; Jacobson et al. 2014. PubMed ID: 24665220). This variant is reported in 0.017% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-2466691-A-AT). Frameshift variants in KCNQ1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 08, 2017

The c.364dupT pathogenic variant in the KCNQ1 gene (also reported as K121fs+162X, 365insT, Ins G 2025-2026, and K121fs/629 due to alternative nomenclature) has previously been reported in individuals referred for LQTS genetic testing (Tester et al., 2005; Kapplinger et al., 2009). The c.364dupT variant causes a shift in reading frame starting at codon cysteine 122, changing it to a leucine, and creating a premature stop codon at position 163 of the new reading frame, denoted p.Cys122LeufsX163. This pathogenic 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 downstream frameshift variants in the KCNQ1 gene have been reported in Human Gene Mutation Database in association with LQTS and JLNS (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.364dupT variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

Long QT syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This sequence change creates a premature translational stop signal (p.Cys122Leufs*163) 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). This variant is present in population databases (rs397508109, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome (PMID: 15840476). This variant is also known as Ins G 2025-2026 (K121fs/629*). ClinVar contains an entry for this variant (Variation ID: 200915). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2019

The c.364dupT pathogenic mutation, located in coding exon 1 of the KCNQ1 gene, results from a duplication of T at nucleotide position 364, causing a translational frameshift with a predicted alternate stop codon (p.C122Lfs*163). This alteration has been detected in the homozygous state in a child of consanguineous parents who was reported to have Jervell and Lange-Nielsen syndrome. The parents were reported to have normal ECGs (Jacobson D et al. Paediatr Child Health, 2014 Mar;19:123-4). This alteration (also referred to as K121fs/629* and 365insT) has also been detected in long QT syndrome genetic testing cohorts; however, details were limited (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). 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. -

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