rs199473400

Variant names:

• chr11-2570716-G-A
• rs199473400
• NM_000218.3:c.566G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2570716-G-A
• chr11-2570716-G-C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000218.3(KCNQ1):​c.566G>A​(p.Gly189Glu) 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. G189R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 6.30
• Publications: 1 publications found

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]

KCNQ1 Gene-Disease associations (from GenCC):

• long QT syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• long QT syndrome 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Jervell and Lange-Nielsen syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P
• atrial fibrillation, familial, 3

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• short QT syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet
• short QT syndrome type 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• familial atrial fibrillation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Jervell and Lange-Nielsen syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 17 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 25 uncertain in NM_000218.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome type 2, long QT syndrome 1, Jervell and Lange-Nielsen syndrome 1, long QT syndrome, short QT syndrome, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy, familial atrial fibrillation, atrial fibrillation, familial, 3.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944
• PP5: Variant 11-2570716-G-A is Pathogenic according to our data. Variant chr11-2570716-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 53068.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNQ1	NM_000218.3	c.566G>A	p.Gly189Glu	missense_variant	Exon 3 of 16	ENST00000155840.12	NP_000209.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNQ1	ENST00000155840.12	c.566G>A	p.Gly189Glu	missense_variant	Exon 3 of 16	1	NM_000218.3	ENSP00000155840.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000654 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Long QT syndrome Pathogenic:2

Dec 10, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566G>A (p.Gly189Glu) variant in the KCNQ1 gene replaces glycine with glutamine at codon 189. This variant has been reported in individuals with long QT syndrome (PMID: 21185501, 21350584, 19490272, 19841300, 17470695, 22949429, 26318259). Experimental studies have shown that this variant has a negative impact on normal protein function (PMID 30571187). Computational models predict a pathogenic impact of this variant on the translated protein (REVEL score: 0.94). ClinVar contains an entry for this variant (ID: 53068). Another variant affecting the same amino acid, p.Gly189Arg has been reported to be likely pathogenic/pathogenic in ClinVar (ID: 3114). This variant is absent in the general population database, gnomAD. Therefore, the c.566G>A (p.Gly189Glu) variant in the KCNQ1 gene is classified as likely pathogenic. -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 189 of the KCNQ1 protein (p.Gly189Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Long QT syndrome (PMID: 17470695, 22949429, 31737537). ClinVar contains an entry for this variant (Variation ID: 53068). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 22456477, 30571187). This variant disrupts the p.Gly189 amino acid residue in KCNQ1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8528244, 10376919, 22373669, 22456477). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Cardiac arrhythmia Pathogenic:1

Mar 18, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with glutamic acid at codon 189 of the KCNQ1 protein. This variant is found within the highly conserved cytoplasmic linker region (a.a. 169-196). A functional study has shown that this variant causes reduced whole-cell current in CHO cells (PMID: 30571187). This variant has been reported in at least four unrelated individuals affected long QT syndrome (PMID: 17470695, 19841300, 21185501, 21350584, 22456477, 22949429, 26318259, 32893267). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Gly189Arg, is known to be pathogenic (ClinVar variation ID 3114), indicating that glycine at this position is important for KCNQ1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -

Cardiovascular phenotype Uncertain:1

Feb 12, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.566G>A (p.G189E) alteration is located in exon 3 (coding exon 3) of the KCNQ1 gene. This alteration results from a G to A substitution at nucleotide position 566, causing the glycine (G) at amino acid position 189 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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:17470695;PMID:19841300). 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
CardioboostArm	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;D;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;M;.
PhyloP100		6.3
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.97, 0.94
MutPred		0.69		.;Gain of sheet (P = 0.0477);.;
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.95
gMVP		0.99
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs199473400; hg19: chr11-2591946;