rs794728527

Positions:

• chr11-2588844-T-A
• chr11-2588844-T-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.1383T>A​(p.Tyr461*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,990 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 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 criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: -0.619

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 11-2588844-T-A is Pathogenic according to our data. Variant chr11-2588844-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 200843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2588844-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1383T>A	p.Tyr461*	stop_gained	10/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1383T>A	p.Tyr461*	stop_gained	10/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.1002T>A	p.Tyr334*	stop_gained	10/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.1026T>A	p.Tyr342*	stop_gained	10/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.843T>A	p.Tyr281*	stop_gained	5/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249076 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459990 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726320

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2021	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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; A different nucleotide change, c.1382dupA, leading to the same nonsense variant has been described in a patient with a mildly prolonged QTc interval in published literature (Kimoto et al., 2013); This variant is associated with the following publications: (PMID: 27761162, 27535533, 24070608) -
Likely pathogenic, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Jun 13, 2012	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. KCNQ1 p.Tyr461Stop Based on the information reviewed below, we agree that it is likely disease-causing. This variant has been previously reported in one Japanese man with mild QT prolongation of 441 msec (Kimoto K et al. 2013). The authors note that the subject was also homozygous for the minor variant of the serine38/glycine 38 polymorphism in KCNE1. No segregation data is available. This is a nonsense mutation, which is predicted to cause loss of normal protein function either due to a prematurely truncated protein or absent protein product resulting from nonsense mediated mRNA decay. 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. Kimoto et al. (2013) characterized this variant in vitro using voltage clamp on transfected HEK-293T cells. They found that cells transfected with this mutant protein showed no delayed rectifying potassium current. Immunoblots of cell lysates showed that the KCNQ1 Tyr461Stop subunit cannot form channel tetramers by itself or with the WT subunit. Also, immunocytochemical analysis showed that the surface expression of this mutant subunit was very low with or without WT subunit present. They conclude that loss of the C-terminal domain of the protein impairs the assembly, trafficking, and function of the mutant subunit-containing channels but does not interfere with expression of the WT channel. -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change creates a premature translational stop signal (p.Tyr461*) 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 (rs794728527, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with mild QT prolongation (PMID: 24070608). ClinVar contains an entry for this variant (Variation ID: 200843). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2018

The p.Y461* pathogenic mutation (also known as c.1383T>A), located in coding exon 10 of the KCNQ1 gene, results from a T to A substitution at nucleotide position 1383. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration was reported in heterozygous state in an individual with a mildly prolonged corrected QTc (Kimoto K et al. Biochem. Biophys. Res. Commun., 2013 Oct;440:283-8). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.087	N
Vest4		0.80
GERP RS		-6.8

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: rs794728527; hg19: chr11-2610074;