11-2777003-G-C

Variant names:

• chr11-2777003-G-C
• rs199472806
• NM_000218.3:c.1703G>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.1703G>C​(p.Gly568Ala) variant causes a missense change involving the alteration of a conserved nucleotide. 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. G568R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 7.70

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 chr11-2777002-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 11-2777003-G-C is Pathogenic according to our data. Variant chr11-2777003-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2777003-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1703G>C	p.Gly568Ala	missense_variant	Exon 14 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1703G>C	p.Gly568Ala	missense_variant	Exon 14 of 16	1	NM_000218.3	ENSP00000155840.2
KCNQ1	ENST00000335475.6	c.1322G>C	p.Gly441Ala	missense_variant	Exon 14 of 16	1		ENSP00000334497.5
KCNQ1	ENST00000496887.7	c.1346G>C	p.Gly449Ala	missense_variant	Exon 14 of 16	5		ENSP00000434560.2
KCNQ1	ENST00000646564.2	c.1163G>C	p.Gly388Ala	missense_variant	Exon 9 of 11			ENSP00000495806.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Jan 01, 2012

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Long QT syndrome Pathogenic:1

Jul 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 568 of the KCNQ1 protein (p.Gly568Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with long QT Syndrome (PMID: 12702160, 27485560). ClinVar contains an entry for this variant (Variation ID: 53010). 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.Gly568 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22456477, 22949429, 22956155, 23392653). 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. -

Cardiovascular phenotype Pathogenic:1

Dec 08, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G568A variant (also known as c.1703G>C), located in coding exon 14 of the KCNQ1 gene, results from a G to C substitution at nucleotide position 1703. The glycine at codon 568 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in individuals with long QT syndrome, including one family with an affected mother and child (Chen S et al. Clin. Genet., 2003 Apr;63:273-82; Vyas B et al. Indian Pacing Electrophysiol J , 2016 Mar;16:8-18). Alternate amino acid substitutions, p.G568R and p.G568E, have also been reported in individuals with LQTS (Tester DJ et al. Heart Rhythm, 2005 May;2:507-17; Izumi G et al. Pediatr Cardiol, 2016 Jun;37:962-70). This amino acid position is highly 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. -

Congenital long QT syndrome Other:1

-

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

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12702160). 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	0.96
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.3	M;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.3	D;.;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	D;.;D
Sift4G	Pathogenic	0.0	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.87
MutPred		0.96		Loss of stability (P = 0.0302);.;.;
MVP		0.97
MPC		1.2
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.90
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

Other links and lift over

dbSNP: rs199472806; hg19: chr11-2798233;