rs147445322

Variant names:

• chr11-2847803-G-A
• rs147445322
• NM_000218.3:c.1831G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2847803-G-A
• chr11-2847803-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.1831G>A is a missense variant that causes replacement of aspartic acid with asparagine at position 611. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001289, with 7/54310 in the Admixed American population, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0004 but higher than the PM2_Supporting threshold of <0.00001, so neither criterion was met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1, however, two probands lacked the required phenotype details for inclusion in PS4_Supporting, so this code is not yet met (PMID:19716085, PMID:19862833, PMID:22727609, PMID:33614747). This variant has been detected in at least 1 individual with Jervell and Lange-Nielsen syndrome who had profound congenital deafness but only a borderline QTc interval of 446 ms, with the variant present in a compound heterozygous state, confirmed in trans with the NM_000218.3:c.546C>A (p.Ser182Arg) variant, which has not yet been classified by the ClinGen Potassium Channel Arrhythmia VCEP (PMID:27917693). The computational predictor REVEL gives a score of 0.593, 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 BP4 threshold of <0.2 and predicts a non-damaging effect on KCNQ1 splicing. The variant does not have a predicted impact on KCNQ1 function in the Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29), due to a limitation of the model (PMID:29021305), so PS3_Supporting is not met. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for long QT syndrome 1 based on the ACMG/AMP criteria applied, as specified by the ClinGen Potassium Channel Arrhythmia VCEP: None. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA006476/MONDO:0100316/112

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:13 B:1 O:1
• Conservation: PhyloP100: 4.89
• Publications: 17 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

Specifications for KCNQ1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.1831G>A	p.Asp611Asn	missense	Exon 16 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.1735G>A	p.Asp579Asn	missense	Exon 15 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.1561G>A	p.Asp521Asn	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.1831G>A	p.Asp611Asn	missense	Exon 16 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.1450G>A	p.Asp484Asn	missense	Exon 16 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.1828G>A	p.Asp610Asn	missense	Exon 16 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000717 AC: 13 AN: 181208 AF XY: 0.0000617

Gnomad AFR exome AF: 0.0000917

Gnomad AMR exome AF: 0.000108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000812

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000761 AC: 108 AN: 1419094 Hom.: 0 Cov.: 31 AF XY: 0.0000755 AC XY: 53 AN XY: 702052

African (AFR) AF: 0.0000307 AC: 1 AN: 32596

American (AMR) AF: 0.000154 AC: 6 AN: 39010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.0000534 AC: 2 AN: 37424

South Asian (SAS) AF: 0.0000866 AC: 7 AN: 80826

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000807 AC: 88 AN: 1089980

Other (OTH) AF: 0.0000681 AC: 4 AN: 58732

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74450

African (AFR) AF: 0.0000482 AC: 2 AN: 41532

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000841 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000117 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	1	Long QT syndrome (5)
1	2	-	Long QT syndrome 1 (3)
-	2	-	not provided (2)
-	2	-	not specified (2)
-	1	-	Cardiac arrhythmia (1)
-	1	-	Cardiovascular phenotype (1)
-	1	-	KCNQ1-related disorder (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
CardioboostArm	Benign	0.00016
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.0074
Eigen_PC	Benign	0.0049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.39	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	0.99	L
PhyloP100		4.9
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.59
Sift	Benign	0.19	T
Sift4G	Benign	0.23	T
Polyphen		0.94	P
Vest4		0.76
MVP		0.95
MPC		0.38
ClinPred		0.034	T
GERP RS		2.9
Varity_R		0.52
gMVP		0.82
Mutation Taster		=21/79	disease causing (ClinVar)

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: rs147445322; hg19: chr11-2869033;