chr11-2768881-C-G

Position:

• chr11-2768881-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP3_Strong PP5

The NM_000218.3(KCNQ1):​c.1552C>G​(p.Arg518Gly) variant causes a missense 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R518P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 1.83

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-2768882-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 11-2768881-C-G is Pathogenic according to our data. 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: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1, Pathogenic=1}. Variant chr11-2768881-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.1552C>G	p.Arg518Gly	missense_variant	12/16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.1552C>G	p.Arg518Gly	missense_variant	12/16	1	NM_000218.3	ENSP00000155840	P1
KCNQ1	ENST00000335475.6	c.1171C>G	p.Arg391Gly	missense_variant	12/16	1		ENSP00000334497
KCNQ1	ENST00000496887.7	c.1195C>G	p.Arg399Gly	missense_variant	12/16	5		ENSP00000434560
KCNQ1	ENST00000646564.2	c.1012C>G	p.Arg338Gly	missense_variant	7/11			ENSP00000495806

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Jul 04, 2018

- -

Long QT syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 16, 2023

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 518 of the KCNQ1 protein (p.Arg518Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of long QT syndrome (PMID: 16414944, 21511995, 24363352; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 52991). 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. For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2016

The c.1552C>G (p.R518G) alteration is located in exon 12 (coding exon 12) of the KCNQ1 gene. This alteration results from a C to G substitution at nucleotide position 1552, causing the arginine (R) at amino acid position 518 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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:16414944). 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	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.;.
Eigen	Benign	0.10
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	M;.;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D;.;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.023	D;.;D
Sift4G	Uncertain	0.010	D;.;D
Polyphen		0.99	D;.;D
Vest4		0.95
MutPred		0.97		Loss of helix (P = 0.0558);.;.;
MVP		0.95
MPC		1.3
ClinPred		0.99	D
GERP RS		-0.65
Varity_R		0.84
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: rs17215500; hg19: chr11-2790111;