11-2572848-G-C

Position:

• chr11-2572848-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.783G>C​(p.Glu261Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E261K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.41

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 topological_domain Cytoplasmic (size 12) in uniprot entity KCNQ1_HUMAN there are 20 pathogenic changes around while only 0 benign (100%) 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 chr11-2572846-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977
• PP5: Variant 11-2572848-G-C is Pathogenic according to our data. Variant chr11-2572848-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 53104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-2572848-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.783G>C	p.Glu261Asp	missense_variant, splice_region_variant	6/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.783G>C	p.Glu261Asp	missense_variant, splice_region_variant	6/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.402G>C	p.Glu134Asp	missense_variant, splice_region_variant	6/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.522G>C	p.Glu174Asp	missense_variant, splice_region_variant	7/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.478-10587G>C		intron_variant				ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 24, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 11530100, 15935335). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 53104). This missense change has been observed in individual(s) with Jervell and Lange-Nielsen syndrome and clinically confirmed long QT syndrome (PMID: 10704188, 11530100, 15840476, 18752142, 23631430, 26675252; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 261 of the KCNQ1 protein (p.Glu261Asp). -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 17, 2023	The c.783G>C (p.Glu261Asp) variant in KCNQ1 gene, that encodes for potassium voltage-gated channel subfamily Q member 1, has been identified in heterozygous status in multiple unrelated individuals (at least 9) with Long QT syndrome (LQTS) (PMID: 15840476, 18752142, 23631430, 26675252) and in one individual affected with Jervell and Lange-Nielsen syndrome (PMID:11140949). This variant has also been observed in compound heterozygous status (with another pathogenic variant p.Glu530*) in two individuals with Jervell and Lange-Nielsen syndrome (JLNS) (PMID: 10704188, 26675252). Expermental studies using Xenopus oocytes showed strong dominant negative effect resulted in pronounced reduction in current amplitude compared to control (PMID: 11530100). When co-expressed with KCNE1 in CHO-K1 and murine myocyte cell line, this variant showed retention of protein to the endoplasmic reticulum and decrease in tail current density (PMID: 15935335). In-silico computational prediction tools suggest that the p.Glu261Aspvariant may have deleterious effect on the protein function (REVEL score: 0.867). This variant is found to be absent in the general population database, gnomAD and interpreted as pathogenic by a submitter in the ClinVar database (ClinVar ID: 53104). Other missense variants substituting the same amino acid (p.Glu261Leu, p.Glu261Gln, p.Glu261Lys) are reported in multiple individuals with LQTS (PMID: 9386136, 19716085, 26669661, 27041096) and classified as likely pathogenic/pathogenic by several submitters in the ClinVar (ClinVar ID: 405253, 67106, 53103). Therefore, the c.783G>C (p.Glu261Asp) variant in the KCNQ1 gene is classified as pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Clinical Genetics Laboratory, Skane University Hospital Lund

Jul 13, 2022

- -

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:10704188;PMID:11530100;PMID:15840476;PMID:18752142;PMID:11140949;PMID:17999538;PMID:15935335). 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	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;D
Vest4		0.97, 0.91
MutPred		0.89		.;Loss of helix (P = 0.0138);.;
MVP		0.98
MPC		1.1
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.95
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

Other links and lift over

dbSNP: rs199472721; hg19: chr11-2594078;