rs762814879

Positions:

• chr11-2528019-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.477+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000106 in 1,610,662 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 8.09

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]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 11-2528019-G-A is Pathogenic according to our data. Variant chr11-2528019-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 200874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2528019-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.477+1G>A		splice_donor_variant		ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.477+1G>A		splice_donor_variant		1	NM_000218.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 34

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251080 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135738

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1458450 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 725834

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: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in skipping of exon 1 and introduces a premature termination codon (PMID: 16987820). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 200874). Disruption of this splice site has been observed in individual(s) with Jervell and Lange-Nielsen syndrome (PMID: 16987820, 19716085, 22629021, 24552659). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs762814879, gnomAD 0.002%). This sequence change affects a donor splice site in intron 2 of the KCNQ1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 22, 2024	This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 2 of the KCNQ1 gene. Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 2, resulting in a premature truncation (PMID: 16987820). This variant has been reported in multiple individuals affected with long QT syndrome (Polyak et al., 2016; Marschall et al., 2019) and in one individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has also been reported in at least four individuals affected with Jervell and Lange-Nielsen syndrome, either in homozygous (PMID: 16987820) or compound heterozygous state (PMID: 22539601, 24552659, 29037160). A few heterozygous family members of these probands have been reported to be asymptomatic for cardiac phenotype (PMID: 16987820, 29037160). This variant has been identified in 2/251080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Dept of Medical Biology, Uskudar University	Jan 08, 2024	Criteria: PVS1_Strong, PS3_Moderate, PM2, PP1 -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	KCNQ1: PVS1, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 19, 2021	Observed in association with LQTS in the published literature (Splawski et al., 2000; Van Langen et al., 2003; Choi et al., 2004; Kapplinger et al., 2009) and in several unrelated individuals referred for genetic testing of LQTS at GeneDx; Not observed at a significant frequency in large population cohorts (gnomAD); Canonical splice donor site variant a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate this variant results in aberrant splicing (Zehelein et al., 2006); This variant is associated with the following publications: (PMID: 9386136, 28264985, 33552729, 19027783, 25525159, 19716085, 10973849, 12566525, 29037160, 22629021, 24552659, 30645170, 31737537, 22539601, 15466642, 26582918, 16987820) -

Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

May 04, 2018

- -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 10, 2020

The c.477+1G>A variant in KCNQ1 has been reported in the heterozygous state in at least in at least 3 individuals with long QT syndrome (LQTS; one of whom also carried another missense variant of uncertain significance in the same gene), and in 1 individual referred for LQTS clinical genetic testing; however, their detailed clinical information was not available (Splawski 2000 PMID: 10973849, Van Langen 2003 PMID: 12566525, Kapplinger 2009 PMID: 19716085). Additionally, it has been reported in 1 individual with swimming triggered arrhythmia (Choi 2004 PMID: 15466642). It has also been reported in the homozygous state or in the compound heterozygous state with another well-established pathogenic variant in at least 3 individuals with with Jervell-Lange-Nielsen syndrome (JLNS) and segregated with disease in 1 affected relative (Zehelein 2006 PMID: 16987820, Winbo 2014 PMID: 24552659, Uysal 2017 PMID: 29037160). Relatives of these individuals, who were heterozygous carriers of this variant, were clinically asymptomatic for LQTS suggesting reduced penetrance and variable expressivity. This variant has been reported by other clinical laboratories in ClinVar (Variation ID: 200874) and has been identified in 0.002% (2/113746) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Furthermore, functional studies using RNA from patients' lymphocytes suggests that this variant causes the skipping of exon 1 skipping and leads to a premature termination codon in exon 4, causing a frameshift which is predicted to lead to a truncated or absent protein. Additionally, this study suggests that this variant impacts protein function, by impairing channel formation and reducing ion current (Zehelein 2006 PMID: 16987820). Loss-of-function variants in KCNQ1 are associated with autosomal dominant LQTS (also known as Romano-Ward syndrome) and autosomal recessive JLNS. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant LQTS (ACMG/AMP criteria applied: PVS1, PS4_supporting, PM2_supporting) and autosomal recessive JLNS (ACMG/AMP criteria applied: PVS1, PM2_Supporting, PM3_Strong). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2023

The c.477+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the KCNQ1 gene. In a study of long QT syndrome (LQTS) clinical genetic testing, this alteration was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). This alteration has also been reported in the homozygous state in siblings with Jervell and Lange-Nielsen syndrome; however, heterozygous family members reportedly did not have LQTS phenotype. The same study reported this alteration to result in altered splicing and premature protein truncation as well as abnormal ion channel function in vitro (Zehelein J et al. J Biol Chem. 2006; 281(46):35397-403). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 06, 2023

This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 2 of the KCNQ1 gene. Functional RNA studies have shown that this variant causes out-of-frame skipping of exon 2, resulting in a premature truncation (PMID: 16987820). This variant has been reported in multiple individuals affected with long QT syndrome (Polyak et al., 2016; Marschall et al., 2019) and in one individual referred for long QT syndrome genetic test (PMID: 19716085). This variant has also been reported in at least four individuals affected with Jervell and Lange-Nielsen syndrome, either in homozygous (PMID: 16987820) or compound heterozygous state (PMID: 22539601, 24552659, 29037160). A few heterozygous family members of these probands have been reported to be asymptomatic for cardiac phenotype (PMID: 16987820, 29037160). This variant has been identified in 2/251080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs762814879; hg19: chr11-2549249;