rs397508120

Positions:

• chr11-2570733-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.585del​(p.Lys196SerfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.64

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-2570733-CG-C is Pathogenic according to our data. Variant chr11-2570733-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 53076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570733-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.585del	p.Lys196SerfsTer41	frameshift_variant	3/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.585del	p.Lys196SerfsTer41	frameshift_variant	3/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.204del	p.Lys69SerfsTer41	frameshift_variant	3/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.324del	p.Lys109SerfsTer41	frameshift_variant	4/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-12700del		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 12, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2020	The KCNQ1 c.585delG; p.Lys196SerfsTer41 variant (rs397508120) is reported in the literature in multiple individuals affected with long QT syndrome (Kapplinger 2009), as well as a proband with Jervell and Lange-Nielsen syndrome in trans to a second pathogenic variant (Wang 2002). The c.585delG variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Kapplinger et al., Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm. 2009 Sep;6(9):1297-303. Wang et al., Compound heterozygous mutations in KvLQT1 cause Jervell and Lange-Nielsen syndrome. Mol Genet Metab. 2002 Apr;75(4):308-16. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 04, 2022	PM2, PM3, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2022	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; This variant is associated with the following publications: (PMID: 22629021, 19716085, 18441444, 25649125, 31229680, 31447099, 34411974, 12051962) -

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2023	For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys196Serfs*41) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Jervell and Lange-Nielsen Syndrome (PMID: 12051962, 19716085). ClinVar contains an entry for this variant (Variation ID: 53076). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 23, 2023	This variant deletes 1 nucleotide in exon 3 of the cytoplasmic linker 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 individuals with suspected long QT syndrome (PMID: 19716085, 31229680). It has also been reported in a biallelic individual with severe phenotype (PMID: 12051962). This variant has not been identified 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. -

Congenital long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 10, 2019

The p.Lys196fs variant has been previously reported in the heterozygous state in 4 individuals referred for genetic testing for long QT syndrome (LQTS; Kapplinger 2009) and in the compound heterozygous state in 1 individual with Jervell and Lange-Nielsen syndrome (JLNS; Wang 2002). It has also been reported by other clinical laboratories in ClinVar (Variant ID# 53076) and is absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 196 and leads to a premature stop codon 41 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Dominant-negative and loss-of-function variants in KCNQ1 cause autosomal dominant LQTS, also known as Romano-Ward syndrome (RWS). In addition, loss of function variants in KCNQ1 also cause autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS). In summary, the p.Lys196fs variant meets criteria to be classified as pathogenic for dominant LQTS and recessive JLNS. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PM3_Supporting -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 17, 2018

The c.585delG pathogenic mutation, located in coding exon 3 of the KCNQ1 gene, results from a deletion of one nucleotide at nucleotide position 585, causing a translational frameshift with a predicted alternate stop codon (p.K196Sfs*41). This mutation was reported in an individual with Jervell and Lange-Nielsen syndrome, who had an additional KCNQ1 variant (Wang Z et al. Mol. Genet. Metab., 2002 Apr;75:308-16). Furthermore, in a study of long QT syndrome clinical genetic testing, this alteration was reported in four patients; however, clinical details were limited (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303). 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. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 18, 2023

This variant deletes 1 nucleotide in exon 3 of the cytoplasmic linker 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 individuals with suspected long QT syndrome (PMID: 19716085, 31229680). It has also been reported in a biallelic individual with severe phenotype (PMID: 12051962). This variant has not been identified 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: -35

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508120; hg19: chr11-2591963;