rs397508118

chr11-2570719-GGCTGC-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000218.3(KCNQ1):c.573_577del(p.Arg192CysfsTer91) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000211 in 1,612,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R190R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16 O:1
• Conservation: PhyloP100: 5.79

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 11-2570719-GGCTGC-G is Pathogenic according to our data. Variant chr11-2570719-GGCTGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 53072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570719-GGCTGC-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3	c.573_577del	p.Arg192CysfsTer91	frameshift_variant	3/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12	c.573_577del	p.Arg192CysfsTer91	frameshift_variant	3/16	1	NM_000218.3	P1
KCNQ1	ENST00000335475.6	c.192_196del	p.Arg65CysfsTer91	frameshift_variant	3/16	1
KCNQ1	ENST00000496887.7	c.312_316del	p.Arg105CysfsTer91	frameshift_variant	4/16	5
KCNQ1	ENST00000646564.2	c.478-12712_478-12708del		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 33

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249462 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135274

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: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1459944 Hom.: 0 AF XY: 0.0000138 AC XY: 10 AN XY: 726396

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: 0.0000252

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74348

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: 0.0000441

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 25, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2022	Observed in the heterozygous state in multiple individuals from different ethnic backgrounds with long QT syndrome (Stattin et al., 2012; Anderson et al., 2014; Seethala et al., 2015; Gaba et al., 2016); Prevalence and haplotype studies suggest it is a founder mutation in the Scandanavian population (Tyson et al., 1997; Winbo et al., 2012); Denoted in published literature as c.735_739delGCGCT, 5 bp deletion of nt 187-191, 572del5, c.572_576del, L191fs/90 and L191fs +90X, due to the use of alternate nomenclature; 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; Published functional studies demonstrate this variant alone did not produce any significant potassium current and had a mild dominant negative when co-expressed with wild-type KCNQ1 channels (Huang et al., 2001); Reported in ClinVar as pathogenic (ClinVar Variant ID# 53072; ClinVar); This variant is associated with the following publications: (PMID: 15466642, 8528244, 31019026, 11530100, 5923041, 26681611, 9328483, 10704188, 11140949, 23098067, 22539601, 24666684, 26675252, 27451284, 23392653, 22677073, 23631430, 19716085, 10973849, 15840476, 30406014, 30369311, 17470695, 10560595, 25471708, 25991456, 18452873, 19841300, 26318259, 31447099, 33087929, 34319147, 34411974) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 17, 2023	The KCNQ1 c.573_577delGCGCT; p.Arg192CysfsTer91 variant (rs397508118), also known as 572del5, 735-739delGCGCT, L191fs/90, or L191fs +90X, is reported in the literature in the homozygous or compound heterozygous state in several individuals and families affected with Jervell and Lange-Nielsen syndrome or in the heterozygous state in individuals with long QT syndrome (Ackerman 1999, Anderson 2015, Giudicessi 2013, Huang 2001), and is a founder variant in the Norwegian population (Tranebjaerg 1999). This variant is also reported in ClinVar (Variation ID: 53072), but is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. In vitro functional analyses demonstrate reduced current and a mild dominant negative effect (Huang 2001). Based on available information, this variant is considered to be pathogenic. References: Ackerman MJ et al. Swimming, a gene-specific arrhythmogenic trigger for inherited long QT syndrome. Mayo Clin Proc. 1999 Nov;74(11):1088-94. PMID: 10560595. Anderson HN et al. Marked, transient, emotion-triggered QT accentuation in an adolescent female with type 1 long QT syndrome. Cardiol Young. 2015 Feb;25(2):376-9. PMID: 24666684. Giudicessi JR and Ackerman MJ. Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. Circ Cardiovasc Genet. 2013 Apr;6(2):193-200. PMID: 23392653. Huang L et al. A spectrum of functional effects for disease causing mutations in the Jervell and Lange-Nielsen syndrome. Cardiovasc Res. 2001 Sep;51(4):670-80. PMID: 11530100. Tranebjaerg L et al. Jervell and Lange-Nielsen syndrome: a Norwegian perspective. Am J Med Genet. 1999 Sep 24;89(3):137-46. PMID: 10704188. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 22, 2016	Testing was performed by GeneDx. We’ve seen this variant in adult in our center with likely long QT syndrome Given the type of variation, the rarity, and the case data we consider this variant likely pathogenic and we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). There are multiple nonsense and frameshift mutations resulting in premature stop codons listed as pathogenic in HGMD and in the NYU/IRCCS Fondazione Salvatore Maugeri Inherited Arrhythmias Database. Of note, ExAC data suggests KCNQ1 is not tolerant to loss of function variation. Fewer variants of that type are observed in the ExAC data than expected. In Familion's case series, 15% of 199 KCNQ1 variants identified on long QT testing were loss of function (Kapplinger et al 2009). Priori's original series had similar rates (Napolitano et al 2005). We have seen multiple loss of function variants in KCNQ1 that we feel are pathogenic. The variant was reported online in 4 of 59916 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of Sep 22nd, 2016). Specifically, the variant was observed in 4 of 32851 Europeans. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Of note, given the observed Norwegian founder effect the allele frequency in a European sample is not necessarily concerning, since Norwegians may well be included in that sample. -

Long QT syndrome 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	Mar 23, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Nov 30, 2017	This frameshifting variant is predicted to lead to early termination of the KCNQ1 protein. There are multiple reports of the variant by clinical laboratories as pathogenic in ClinVar (Variation ID 53072) and in the literature (PMID: 24666684, 11530100, 10560595). Truncating variants in KCNQ1 are established as disease causing, and the variant is predicted by in silico methods to be damaging. Functional characterization of the variant indicated electrophysiological consequences on channel functioning (PMID: 11530100). It is seen in 2 heterozygotes in gnomAD, thus the variant is rare. Based on the combined evidence, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Region Ostergotland	Oct 12, 2020	PVS1, PM2, PP5 -

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 04, 2023	This sequence change creates a premature translational stop signal (p.Arg192Cysfs*91) 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 (rs764567762, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with long QT syndrome (PMID: 10560595, 11530100, 22539601, 23392653, 24666684). ClinVar contains an entry for this variant (Variation ID: 53072). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	Jan 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 07, 2023	This variant (also known as 572del5 and c.572_576del in published literature due to the use of alternate nomenclature) deletes 5 nucleotides in exon 3 of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A functional study has shown that this variant does not produce any significant potassium current and has a mild dominant negative effect when co-expressed with wild-type KCNQ1 channels in Xenopus laevis oocytes (PMID: 11530100). This variant has been reported in homozygous or compound heterozygous states in many individuals affected with Jervell and Lange-Nielsen syndrome from 15 different families of Norwegian or Swedish ancestry, and in heterozygous state in 3 relatives affected with long QT syndrome and in 29 asymptomatic relatives from these families (PMID: 10704188, 22539601, 25471708, 27451284, 30406014). This variant has also been reported in another 8 unrelated individuals affected with long QT syndrome (PMID: 24666684, 30369311, 31246743, 31520628, 32893267). This variant has been identified in 4/249462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2016	Variant summary: The KCNQ1 c.573_577delGCGCT (p.Arg192Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent KCNQ1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 4/120312 control chromosomes at a frequency of 0.0000332, which does not exceed the estimated maximal expected allele frequency of a pathogenic KCNQ1 variant (0.0000833). The variant is recurrently reported in patients with JLNS in homozygous as well as heterozygous state. The variant is also reported in heterozygous state in LQTS patients or in individuals suspected of LQTS diagnosis, in individuals with normal or borderline QTS prolongation, atrial fibrillation and sudden unexplained death, suggesting that clinical features associated with a heterozygous c.573_577delGCGCT variant are variable. Functional data are consistent with disease-causing role of this variant. It has also been reported as a probable founder/common mutation in Norway and Sweden causing JLNS. One clinical labs in ClinVar as well as reputable databases have classified it as pathogenic. Taken together, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 17, 2023	The c.573_577delGCGCT pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of 5 nucleotides at positions 573 to 577, causing a translational frameshift with a predicted alternate stop codon (p.R192Cfs*91). This alteration has been described in several homozygous and compound heterozygous families with autosomal recessive Jervell and Lange-Nielsen syndrome, and haplotype analysis has suggested a founder mutation effect in Norway (Tranebjaerg L et al. Am J Med Genet. 1999;89:137-46). Among these families, this alteration also was detected in the heterozygous state in multiple unaffected relatives; however, in other studies, this alteration was reported in heterozygous individuals with autosomal dominant long QT syndrome (LQTS) (Ackerman MJ et al. Mayo Clin Proc.1999;74:1088-94; Anderson HN et al. Cardiol Young. 2015;25:376-9), suggesting co-segregation with incomplete penetrance. In addition to the clinical data presented in the literature, 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 1;C4551647:Long QT syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Oct 08, 2018

The c.573_577delGCGCT (p. Arg192Cysfs*91) variant in the KCNQ1 gene was predicted to produce a truncated protein. It has been observed in multiple individuals with long QT syndrome and was segregated in a Norwegian family with Long QT syndrome (PMID: 10704188, 11530100, 23392653). This variant is extremely rare in the general population according to gnomAD database. Therefore, this c.573_577delGCGCT (p. Arg192Cysfs*91) variant in the KCNQ1 gene is classified as pathogenic. -

Jervell and Lange-Nielsen syndrome;C1141890:Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2017

The p.Arg192CysfsX91 variant is reported to be a Scandinavian founder variant in KCNQ1 and has been identified in the homozygous or compound heterozygous state in at least 10 individuals from 9 families with Jervell and Lange-Nielsen syndro me (JLNS). Most of the older relatives who were heterozygous carriers of this va riant were asymptomatic with normal QT intervals, while at least 3 had clinical features of long QT syndrome (LQTS; Tranebjareg 1999, Winbo 2012), indicating re duced penetrance. This variant has also been identified in at least 4 unrelated individuals with LQTS (Ackerman 1999, Lieve 2013, Anderson 2015) and has been re ported in ClinVar (Variation ID: 53072). In vitro functional studies provide som e evidence that the p.Arg192CysfsX91 variant may slightly impact protein functio n (Huang 2001). Additionally, this variant has been identified in 4/113014 of Eu ropean chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 192 and leads to a premature termination codon 91 amino a cids downstream. This alteration is then predicted to lead to a truncated or abs ent protein. Loss-of-function variants in KCNQ1 are associated with LQTS (also k nown as Romano-Ward syndrome) in the heterozygous state and with JLNS in the com pound heterozygous or homozygous state. In summary, this variant meets criteria to be classified as pathogenic for LQTS in an autosomal dominant manner with red uced penetrance and JLNS in an autosomal recessive manner. ACMG/AMP criteria: PV S1, PS4, PM2. -

KCNQ1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

-

This frameshifting variant in exon 3 of 16 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in multiple individuals with long QT syndrome (PMID: 10560595, 22539601, 24666684, 11530100, 23392653). Functional studies showed the c.573_577del (p.Arg192CysfsTer91) variant causes a dominant-negative effect on KCNQ1 function (PMID: 11530100). The c.573_577del (p.Arg192CysfsTer91) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (4/249462) and thus is presumed to be rare. Based on the available evidence, the c.573_577del (p.Arg192CysfsTer91) variant is classified as Pathogenic. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 01, 2023

This variant (also known as 572del5 and c.572_576del in published literature due to the use of alternate nomenclature) deletes 5 nucleotides in exon 3 of the KCNQ1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in homozygous or compound heterozygous states in many individuals affected with Jervell and Lange-Nielsen syndrome from 15 different families of Norwegian or Swedish ancestry, and in heterozygous state in 3 relatives affected with long QT syndrome and in 29 asymptomatic relatives from these families (PMID: 10704188, 22539601, 25471708, 27451284, 30406014). This variant has also been reported in another 8 unrelated individuals affected with long QT syndrome (PMID: 24666684, 30369311, 31246743, 31520628, 32893267). This variant has been identified in 4/249462 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of KCNQ1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Jervell and Lange-Nielsen syndrome 1 Other:1

not provided, no classification provided

literature only

GeneReviews

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508118; hg19: chr11-2591949;