rs199472794

Positions:

• chr11-2775985-G-A
• chr11-2775985-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.1616G>A​(p.Arg539Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. R539W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 4.52

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.

• PM1: In a region_of_interest Interaction with KCNE1 C-terminus (size 37) in uniprot entity KCNQ1_HUMAN there are 36 pathogenic changes around while only 1 benign (97%) in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2775984-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952
• PP5: Variant 11-2775985-G-A is Pathogenic according to our data. Variant chr11-2775985-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2775985-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.1616G>A	p.Arg539Gln	missense_variant	13/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1616G>A	p.Arg539Gln	missense_variant	13/16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.1235G>A	p.Arg412Gln	missense_variant	13/16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.1259G>A	p.Arg420Gln	missense_variant	13/16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.1076G>A	p.Arg359Gln	missense_variant	8/11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1416252 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 699848

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 14, 2017

The KCNQ1 Arg539Gln has been reported previously in a case control study of 2500 patients referred for long QT genetic testing (Kapplinger JD, et al., 2009), as well as a long QT patient (Cardiovascular Biomedical Research Unit Royal Brompton & Harefield NHS Foundation Trust ClinVar: SCV000089124). Interestingly, another rare variant at this position (KCNQ1 Arg539Trp) has been classified as pathogenic; suggesting that an amino acid substitution at this site may not be tolerated. We have identified this KCNQ1 Arg539Gln variant in one long QT case, and the variant was found to segregate to another affected family member. The variant is absent in the 1000 genomes project (http://www.1000genomes.org/), as well as the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Computational tools SIFT, MutationTaster, and PolyPhen-2 predict this variant to have a deleterious effect. This variant was discussed at our multidisciplinary pathogenicity meeting and based on rarity in the general population, pathogenic classification of another amino acid substitution at the same position, our familial data, in silico tools supportive of a deleterious effect and because the proband has a typical LQT1 phenotype which is known to be caused by genetic variation in only the KCNQ1 gene, we classify KCNQ1 Arg539Gln as "likely pathogenic". -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 18, 2024

Reported in one individual with sudden cardiac arrest and a clinical diagnosis of Jervell and Lange-Nielsen syndrome and in individuals referred for LQTS genetic testing at GeneDx and in published literature (PMID: 28566242, 27920829, 19716085); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19716085, 27920829, 28566242, 36243179) -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg539 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23098067, 23251633, 23631430, 24681627, 25559286). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 67042). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 19716085; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 539 of the KCNQ1 protein (p.Arg539Gln). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2024

The p.R539Q variant (also known as c.1616G>A), located in coding exon 13 of the KCNQ1 gene, results from a G to A substitution at nucleotide position 1616. The arginine at codon 539 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in individuals with concerns for long QT syndrome, including individuals with sudden cardiac arrest (Kapplinger JD et al. Heart Rhythm, 2009 Sep;6:1297-303; Burns C et al. J Arrhythm, 2016 Dec;32:456-461; Jiménez-Jáimez J et al. Rev Esp Cardiol (Engl Ed), 2017 Oct;70:808-816; Walsh R et al. Genet Med, 2021 Jan;23:47-58; Ambry internal data). Based on internal structural analysis, this alteration disrupts the interaction with PIP2 which stabilizes the channel open state (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

May 28, 2019

This missense variant replaces arginine with glutamine at codon 539 in the C-terminal cytoplasmic domain of the KCNQ1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in multiple individuals referred for long QT syndrome genetic testing (PMID: 19716085) or affected with long QT syndrome (PMID: 27920829, 28566242). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the the same codon (p.Arg539Trp) is known to cause long QT syndrome (Clinvar variation ID 52998), suggesting that arginine at this position is important for the protein function. Based on available evidence, this variant is classified as Likely Pathogenic. -

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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;.;.
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.1	D;.;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.013	D;.;D
Sift4G	Uncertain	0.029	D;.;D
Polyphen		1.0	D;.;D
Vest4		0.87
MutPred		0.78		Loss of MoRF binding (P = 0.0481);.;.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.59
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199472794; hg19: chr11-2797215; COSMIC: COSV99030387; COSMIC: COSV99030387;