rs199473483

Positions:

chr11-2778014-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The NM_000218.3(KCNQ1):c.1771C>T(p.Arg591Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,422 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R591H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1O:1

Conservation

PhyloP100: 1.92

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 21) in uniprot entity KCNQ1_HUMAN there are 19 pathogenic changes around while only 0 benign (100%) in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2778015-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 11-2778014-C-T is Pathogenic according to our data. Variant chr11-2778014-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53016.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2778014-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1771C>T	p.Arg591Cys	missense_variant	15/16	ENST00000155840.12	NP_000209.2	P51787-1Q96AI9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1771C>T	p.Arg591Cys	missense_variant	15/16	1	NM_000218.3	ENSP00000155840.2		P51787-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251012

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.00000684

AC:

AN:

1461422

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727038

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000882

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 27, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 591 of the KCNQ1 protein (p.Arg591Cys). This variant is present in population databases (rs199473483, gnomAD 0.006%). This missense change has been observed in individuals with long QT syndrome (PMID: 17470695, 19716085, 22429796, 22727609, 22949429). ClinVar contains an entry for this variant (Variation ID: 53016). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNQ1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg591 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10024302, 16253915, 19261104, 21482651, 22949429). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 01, 2024	This missense variant replaces arginine with cysteine at codon 591 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region at C-terminus (a.a. 509-575). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study using Xenopus oocytes has shown that this variant causes a significant decrease in current amplitudes compared to wildtype KCNQ1 channels (PMID: 36674868). This variant has been reported in at least 7 unrelated individuals affected with long QT syndrome (PMID: 22429796, 22727609, 26318259, 31520628, 36674868), in a few individuals suspected of having long QT syndrome (PMID:19716085, 23631430, 26743238), and in several individuals affected with sudden death (PMID: 17470695). This variant has been identified in 1/251012 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, Arg591His, is known to be pathogenic (ClinVar variation ID 53017), indicating that arginine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Long QT syndrome 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

PM2_Supporting+PM5+PP3_Strong+PS4_Supporting -

Cardiac arrhythmia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Oct 25, 2023

This missense variant replaces arginine with cysteine at codon 591 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant is found within a highly conserved region at C-terminus (a.a. 509-575). Rare non-truncating variants in this region have been shown to be significantly overrepresented in individuals with long QT syndrome (PMID: 32893267). A functional study using Xenopus oocytes has shown that this variant causes a significant decrease in current amplitudes compared to wildtype KCNQ1 channels (PMID: 36674868). This variant has been reported in at least 7 unrelated individuals affected with long QT syndrome (PMID: 22429796, 22727609, 26318259, 31520628, 36674868), in a few individuals suspected of having long QT syndrome (PMID:19716085, 23631430, 26743238), and in several individuals affected with sudden death (PMID: 17470695). This variant has been identified in 1/251012 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, Arg591His, is known to be pathogenic (ClinVar variation ID 53017), indicating that arginine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided

Uncertain:1

Uncertain significance, flagged submission

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Jun 15, 2020

- -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:17470695;PMID:19716085;PMID:19841300;PMID:22429796). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;.;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.85

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

3.0

M;.;.;.

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-5.7

D;.;D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;.

Polyphen

1.0

D;.;D;.

Vest4

0.96

MutPred

0.90

Loss of MoRF binding (P = 0.0053);.;.;.;

MVP

0.97

MPC

1.4

ClinPred

0.99

GERP RS

3.1

Varity_R

0.67

gMVP

0.99

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