11-2570652-G-C

Position:

• chr11-2570652-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PS1 PM2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.502G>C​(p.Gly168Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,328 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 9.44

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.

• PS1: Transcript NM_000218.3 (KCNQ1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 11-2570652-G-C is Pathogenic according to our data. Variant chr11-2570652-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 53053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2570652-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.502G>C	p.Gly168Arg	missense_variant	3/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.502G>C	p.Gly168Arg	missense_variant	3/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.121G>C	p.Gly41Arg	missense_variant	3/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.241G>C	p.Gly81Arg	missense_variant	4/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-12783G>C		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249646 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135384

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: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460328 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726574

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	Jun 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 08, 2023	The c.502G>C (p.Gly168Arg) variant in the KCNQ1 gene has been identified in multiple individuals affected with Long QT syndrome (LQTS) (PMID:9386136, 36102233, 33256261, 27921062, 26743238, 24103226, 23995044). This variant, and another variant resulting in the same amino acid substitution c.502G>A (p.Gly168Arg), has been observed in multiple individuals referred for the long QT syndrome genetic testing (PMID: 19716085), and reported to segregate with disease in three families with more than ten affected individuals (PMID: 9693036). The other variant resulting in the same amino acid substitution, c.502G>A (p.Gly168Arg), is a well-known disease-causing variant reported in multiple individuals (>15) with LQTS (PMID: 9693036, 20186784, 10973849, 29952348, 12402336, 17905336, 27485560, 19841300, 22949429). In vitro functional studies on HEK293 cells and X. laevis oocytes have demonstrated that this missense substitution p.Gly168Arg affects KCNQ1 channel function and cause reduced channel current (PMID: 22456477, 15051636). In-silico computational prediction tools suggest that the p.Gly168Arg variant may have deleterious effect on the protein function (REVEL score: 0.937). This variant is found to be rare (1/249646; 0.000004) in the general population database (gnomAD) and interpreted as pathogenic by several submitters in the ClinVar database (ClinVar ID: 53053). Therefore, the c.502G>C (p.Gly168Arg) variant in the KCNQ1 gene is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 02, 2023	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 168 of the KCNQ1 protein (p.Gly168Arg). This variant is present in population databases (rs179489, gnomAD 0.0009%). This missense change has been observed in individuals with long QT syndrome (PMID: 9386136, 9693036, 10973849, 17905336, 19841300; Invitae). ClinVar contains an entry for this variant (Variation ID: 53053). 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%. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 15051636, 22456477). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Dec 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2022	Observed in multiple unrelated individuals with LQTS referred for genetic testing at GeneDx and in published literature (Donger et al., 1997; Kapplinger et al., 2009); 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; Published functional studies demonstrate that p.(G168R) (nucleotide change not specified) results in lost or reduced channel function (Westenskow et al., 2004; Jons et al., 2011); This variant is associated with the following publications: (PMID: 19716085, 26681611, 28749187, 17091796, 20186784, 27041150, 24103226, 12566525, 14678125, 19490272, 23995044, 21185501, 26318259, 25479336, 9693036, 14531214, 27485560, 10973849, 22949429, 17470695, 22456477, 21451124, 27921062, 33256261, 15051636, 9386136) -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2022

The p.G168R pathogenic mutation (also known as c.502G>C), located in coding exon 3 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 502. The glycine at codon 168 is replaced by arginine, an amino acid with dissimilar properties. This alteration, and another nucleotide substitution resulting in the same amino acid change (c.502G>A), has been detected in multiple unrelated heterozygous individuals reported to have long QT syndrome (LQTS), has been reported to segregate with LQTS in multiple families, and has been reported in the homozygous state in association with Jervell and Lange-Nielsen syndrome (Donger C et al. Circulation. 1997;96(9):2778-81; Splawski I et al. Genomics. 1998;51(1):86-97; Splawski I et al. Circulation. 2000;102(10):1178-85; Márquez MF et al. Arch Cardiol Mex. 2006;76(3):257-62; Kapplinger JD et al. Heart Rhythm. 2009;6(9):1297-303; Summers KM et al. Am J Med Genet. 2010;152A(3):613-21; Vyas B. Am. J Med Genet A. 2016;170(6):1510-9; Yoshinaga M et al. Circ J. 2018;82(8):2152-2159). In addition, this alteration has been reported to result in loss of ion channel function in vitro (Westenskow P et al. Circulation. 2004;109(15):1834-41). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

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:9386136;PMID:19716085;PMID:9693036;PMID:12402336;PMID:14531214;PMID:12566525;PMID:17091796;PMID:17470695;PMID:15051636). 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	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.98, 0.95
MutPred		0.90		.;Gain of methylation at G168 (P = 0.0225);.;
MVP		0.98
MPC		2.5
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.96
gMVP		0.99

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: rs179489; hg19: chr11-2591882;