11-2847958-C-G

Position:

chr11-2847958-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate

The NM_000218.3(KCNQ1):c.1986C>G(p.Tyr662Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,564,530 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y662Y) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: -2.57

Variant links:

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]

KCNQ1 links:

KCNQ1-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

KCNQ1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0222 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1986C>G	p.Tyr662Ter	stop_gained	16/16	ENST00000155840.12	NP_000209.2
KCNQ1-AS1	NR_130721.1 linkuse as main transcript	n.778-7516G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1986C>G	p.Tyr662Ter	stop_gained	16/16	1	NM_000218.3	ENSP00000155840	P1	P51787-1
KCNQ1-AS1	ENST00000440887.2 linkuse as main transcript	n.777-7516G>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000504

AC:

AN:

178672

Hom.:

AF XY:

0.0000522

AC XY:

AN XY:

95804

show subpopulations

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:

0.000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000210

AC:

297

AN:

1412468

Hom.:

Cov.:

AF XY:

0.000205

AC XY:

143

AN XY:

697324

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

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:

0.000254

Gnomad4 OTH exome

AF:

0.000343

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152062

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74264

show subpopulations

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:

0.000103

Gnomad4 OTH

AF:

0.00

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000341

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 24, 2023	This sequence change creates a premature translational stop signal (p.Tyr662*) in the KCNQ1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the KCNQ1 protein. This variant is present in population databases (rs11601907, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with clinical features of KCNQ1-related conditions (PMID: 19716085, 26704558, 34495297). This variant is also known as c.1605C>G, p.Tyr535Ter. ClinVar contains an entry for this variant (Variation ID: 200864). This variant disrupts a region of the KCNQ1 protein in which other variant(s) (p.Asp673Gly) have been observed in individuals with KCNQ1-related conditions (PMID: 32383558). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 08, 2024	This variant changes 1 nucleotide in exon 16 of the KCNQ1 gene, creating a premature translation stop signal in the last coding exon. This variant is expected to escape nonsense-mediated decay and expressed as a truncated protein product missing the last 15 amino acids of the KCNQ1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085), in an individual affected with epilepsy and sudden death (PMID: 26704558), and in an individual affected with sudden infant death (PMID: 37589201). This variant has also been identified in 12/209918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2017

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is in the last exon of KCNQ1. It has been reported in one individual with LQTS (Kapplinger 2009). The variant has a Max MAF of 0.02% in ExAC (3 alleles) and 0.01% in gnomAD (10 alleles). It is classified in ClinVar with 1 star as Pathogenic by GeneDx. -

KCNQ1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The KCNQ1 c.1986C>G (p.Tyr662Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. The p.Tyr662Ter variant has been reported in two studies in which it is found in a two individuals in a heterozygous state (Kapplinger et al. 2009; Bagnall et al. 2016). One individual was suspected of having long QT syndrome and the other was evaluated due to sudden unexpected death in epilepsy. The p.Tyr662Ter variant was absent from 1300 controls and is reported at a frequency of 0.00017 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Tyr662Ter variant is therefore classified as a variant of unknown significance, but suspicious for pathogenicity for KCNQ1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2024

Nonsense variant predicted to result in protein truncation as the last 15 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 26704558, 28775708, 34495297, 19716085) -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 08, 2023

This variant changes 1 nucleotide in exon 16 of the KCNQ1 gene, creating a premature translation stop signal in the last coding exon. This variant is expected to escape nonsense-mediated decay and expressed as a truncated protein product missing the last 15 amino acids of the KCNQ1 protein. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual referred for long QT syndrome testing (PMID: 19716085), in an individual affected with epilepsy and sudden death (PMID: 26704558), and in an individual affected with sudden infant death (PMID: 37589201). This variant has also been identified in 12/209918 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jervell and Lange-Nielsen syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Short QT syndrome type 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.26

MutationTaster

Benign

1.0

D;D

Vest4

0.84

GERP RS

-2.3

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over