rs145974930

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM5

The NM_000218.3(KCNQ1):c.1553G>A(p.Arg518Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000126 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8O:1

Conservation

PhyloP100: 4.80

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000218.3

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-2768881-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52991.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNQ1	NM_000218.3 linkuse as main transcript	c.1553G>A	p.Arg518Gln	missense_variant	12/16	ENST00000155840.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNQ1	ENST00000155840.12 linkuse as main transcript	c.1553G>A	p.Arg518Gln	missense_variant	12/16	1	NM_000218.3	P1	P51787-1
KCNQ1	ENST00000335475.6 linkuse as main transcript	c.1172G>A	p.Arg391Gln	missense_variant	12/16	1			P51787-2
KCNQ1	ENST00000496887.7 linkuse as main transcript	c.1196G>A	p.Arg399Gln	missense_variant	12/16	5
KCNQ1	ENST00000646564.2 linkuse as main transcript	c.1013G>A	p.Arg338Gln	missense_variant	7/11

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251410

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

197

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000132

AC XY:

AN XY:

727214

show subpopulations

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:

0.000177

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152072

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000966

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000435

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:3

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 518 of the KCNQ1 protein (p.Arg518Gln). This variant is present in population databases (rs145974930, gnomAD 0.005%). This missense change has been observed in individual(s) with sudden infant death syndrome and in individuals with QT intervals in the normal range (PMID: 26159999, 29544605). ClinVar contains an entry for this variant (Variation ID: 67036). 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 not expected to disrupt KCNQ1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect KCNQ1 function (PMID: 26546361). This variant disrupts the p.Arg518 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16414944, 21511995, 24363352; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue 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	Dec 01, 2023	This missense variant replaces arginine with glutamine at codon 518 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). Functional studies have shown that this variant does not affect the ability of KCNQ1 protein to regulate renal ciliogenesis (PMID: 19716085, 26546361). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 29544605) and in several individuals referred for long QT syndrome genetic testing (PMID: 19716085, 26159999). Mean QTc interval of the carriers was not significantly different from that of non-carriers (PMID: 26159999). This variant has also been reported in one individual affected with cardiac arrest; however, the sibling who also carried the variant was asymptomatic (PMID: 31994352). This variant has been identified in 9/282772 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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 24, 2022

Variant summary: KCNQ1 c.1553G>A (p.Arg518Gln) results in a conservative amino acid change located in the Potassium channel, voltage dependent, KCNQ, C-terminal domain (IPR013821) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1553G>A has been reported in the literature in individuals affected with Long QT syndrome, sudden infant death, epilepsy and hypertrophic cardiomyopathy (examples: Kapplinger_2009, Costa_2012, Lieve_2013, Ghouse_2015, Ruwald_2016, Tester_2018, Li_2019, Dai_2021). In addition, the variant was found to co-occur with a pathogenic RYR2 variant (c.527G>T, p.Arg176Leu) in a female affected with cardiac arrest and her brother exhibiting catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype. Their mother who was also affected with cardiac arrest was found to only carry the RYR2 variant, as were multiple symptomatic members from the maternal side of the family. The authors concluded that the RYR2 variant was predisposing to low penetrant CPVT in this family (Tung_2020). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmia. At least one publication reports experimental evidence evaluating an impact on protein function. Slaats_2015 demonstrated that KCNQ1-p.R518Q variant could rescue ciliogenecis defect to the same levels as wild-type. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 03, 2022

Observed in individuals with Long QT syndrome and sudden infant death syndrome in the published literature (Kapplinger et al., 2009; Ghouse et al., 2015; Tester et al., 2018); Published functional studies demonstrate the R518Q variant retains function and have suggested this is a benign variant (Slaats et al., 2015); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22581653, 25637381, 25854863, 26159999, 32048431, 26546361, 29544605, 19716085, 31994352, 27535533) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 01, 2022

The c.1553G>A (p.R518Q) alteration is located in exon 12 (coding exon 12) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 1553, causing the arginine (R) at amino acid position 518 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Cardiac arrhythmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 06, 2023

This missense variant replaces arginine with glutamine at codon 518 of the KCNQ1 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. This variant is found within a highly conserved C-terminus region (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). Functional studies have shown that this variant does not affect the ability of KCNQ1 protein to regulate renal ciliogenesis (PMID: 19716085, 26546361). This variant has been reported in an individual affected with sudden infant death syndrome (PMID: 29544605) and in several individuals referred for long QT syndrome genetic testing (PMID: 19716085, 26159999). Mean QTc interval of the carriers was not significantly different from that of non-carriers (PMID: 26159999). This variant has also been reported in one individual affected with cardiac arrest; however, the sibling who also carried the variant was asymptomatic (PMID: 31994352). This variant has been identified in 9/282772 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. -

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:19716085). 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

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.9

D;.;D

REVEL

Pathogenic

0.72

Sift

Benign

0.060

T;.;D

Sift4G

Benign

0.095

T;.;T

Polyphen

0.78

P;.;P

Vest4

0.82

MVP

0.96

MPC

0.93

ClinPred

0.52

GERP RS

4.3

Varity_R

0.69

gMVP

0.98

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