rs530612385

Positions:

• chr11-2570714-G-A
• chr11-2570714-G-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.564G>A​(p.Trp188Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.23

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 11-2570714-G-A is Pathogenic according to our data. Variant chr11-2570714-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 263738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570714-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.564G>A	p.Trp188Ter	stop_gained	3/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.564G>A	p.Trp188Ter	stop_gained	3/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.183G>A	p.Trp61Ter	stop_gained	3/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.303G>A	p.Trp101Ter	stop_gained	4/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-12721G>A		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460076 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726454

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 04, 2024	The c.564G>A (p.Trp188*) variant in the KCNQ1 gene creates a premature translational stop codon in the KCNQ1 gene. It is predicted to result in an absent or disrupted protein product. Loss-of-function variants in KCNQ1 are known to be pathogenic (PMID: 9323054, 19862833). This premature translational stop signal has been observed in individual(s) with clinical features of long QT syndrome (PMID: 19716085, PMID: 26318259). This variant is absent in the general population database (gnomAD). ClinVar contains an entry for this variant (Variation ID: 263738). Based on the available evidence the c.564G>A (p.Trp188*) variant in the KCNQ1 gene is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2023	This sequence change creates a premature translational stop signal (p.Trp188*) 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 individual(s) with clinical features of long QT syndrome (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 263738). For these reasons, this variant has been classified as Pathogenic. -

Long QT syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)

Apr 01, 2023

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 22, 2022

Reported in an individual with Long QT syndrome in published literature (Kapplinger et al., 2009); clinical information is limited; Nonsense 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19716085) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2015

The p.W188* pathogenic mutation (also known as c.564G>A), located in coding exon 3 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 564. This changes the amino acid at codon 188 from a tryptophan to a stop codon. In a study of long QT syndrome clinical genetic testing, this nonsense pathogenic mutation was reported in one patient (Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303). In addition, nonsense mutations in the KCNQ1 gene have been described in multiple individuals with long QT syndrome and arrhythmias, demonstrating truncation mutations are pathogenic for disease. In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A
Vest4		0.91, 0.90
GERP RS		4.4

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

Other links and lift over

dbSNP: rs530612385; hg19: chr11-2591944;