rs1800172

Variant names:

• chr11-2847899-G-A
• rs1800172
• NM_000218.3:c.1927G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2847899-G-A
• chr11-2847899-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.1927G>A is a missense variant predicted to cause substitution of glycine by serine at amino acid 643 (p.Gly643Ser). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.04778, with 2,047 alleles / 42,844 total alleles and 53 homozygotes in the East Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BA1 threshold of >0.004 (BA1). This variant has been identified in individuals with LQTc interval including 3 who had QTc interval over 480ms, as well as an individual with sudden unexplained death, however their phenotypes do not meet criteria for being highly specific to LQTS (PMID 15028050; PMID:26385840). The variant is seen frequently in control individuals vs cases (PMID:26159999; PMID:18426444). From in-vitro studies, this variant is thought to have a weak dominant-negative effect without much alteration to its kinetic properties (PMID:11761407; PMID:22378279). This variant is thought to be a risk factor/predisposition to arrhythmias or acquired LQTS, but is not thought to be a risk factor for congenital LQTS. The computational predictor REVEL gives a score of 0.566, which is below the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.75 but higher than the BP4 threshold of <0.25 and does not strongly predict a damaging effect on KCNQ1 function. The computational splicing predictor SpliceAI gives a score of 0.00, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.2 and does not strongly predict a damaging effect on KCNQ1 splicing. In summary, this variant meets the criteria to be classified as benign for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmias VCEP: BA1. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA006598/MONDO:0100316/112

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (56 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Benign reviewed by expert panel B:19 O:1
• Conservation: PhyloP100: -4.71
• Publications: 50 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-AS1 (HGNC:42790): (KCNQ1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.1927G>A	p.Gly643Ser	missense	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1831G>A	p.Gly611Ser	missense	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1657G>A	p.Gly553Ser	missense	Exon 17 of 17	NP_001393766.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1927G>A	p.Gly643Ser	missense	Exon 16 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1546G>A	p.Gly516Ser	missense	Exon 16 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1924G>A	p.Gly642Ser	missense	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.00789 AC: 1201 AN: 152152 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0425

Gnomad SAS AF: 0.00993

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00616 AC: 1198 AN: 194370 AF XY: 0.00570

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0474

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000182

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00242 AC: 3451 AN: 1428030 Hom.: 56 Cov.: 31 AF XY: 0.00251 AC XY: 1772 AN XY: 707262

African (AFR) AF: 0.0208 AC: 680 AN: 32686

American (AMR) AF: 0.00137 AC: 56 AN: 40838

Ashkenazi Jewish (ASJ) AF: 0.0000393 AC: 1 AN: 25464

East Asian (EAS) AF: 0.0485 AC: 1826 AN: 37674

South Asian (SAS) AF: 0.00703 AC: 576 AN: 81914

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5716

European-Non Finnish (NFE) AF: 0.000131 AC: 144 AN: 1095358

Other (OTH) AF: 0.00271 AC: 160 AN: 58988

GnomAD4 genome AF: 0.00792 AC: 1206 AN: 152270 Hom.: 17 Cov.: 33 AF XY: 0.00802 AC XY: 597 AN XY: 74464

African (AFR) AF: 0.0208 AC: 863 AN: 41548

American (AMR) AF: 0.00346 AC: 53 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0427 AC: 221 AN: 5170

South Asian (SAS) AF: 0.00994 AC: 48 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68002

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00365 Hom.: 6

Bravo AF: 0.00875

ESP6500AA AF: 0.0195 AC: 84

ESP6500EA AF: 0.000472 AC: 4

ExAC AF: 0.00591 AC: 701

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (5)
-	-	3	Long QT syndrome 1 (3)
-	-	2	Cardiac arrhythmia (2)
-	-	1	Atrial fibrillation, familial, 3 (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Jervell and Lange-Nielsen syndrome 1 (1)
-	-	1	Long QT syndrome (1)
-	-	1	Short QT syndrome type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	0.016
DANN	Benign	0.88
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0044	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0035	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.0	N
PhyloP100		-4.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.76	N
REVEL	Uncertain	0.57
Sift	Benign	0.58	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.080
MVP		0.67
MPC		0.37
ClinPred		0.0055	T
GERP RS		-2.9
Varity_R		0.032
gMVP		0.33
Mutation Taster		=77/23	polymorphism

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: rs1800172; hg19: chr11-2869129; COSMIC: COSV50110156;