rs199472676

Variant names:

• chr11-2445315-C-A
• rs199472676
• NM_000218.3:c.217C>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2445315-C-A
• chr11-2445315-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PS4_Moderate BP5

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.217C>A (p.Pro73Thr) is a missense variant that causes substitution of proline with threonine at amino acid 73. This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0002533, with 287 alleles / 1132988 total alleles in the European non-Finnish population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP PM2_Supporting threshold of <0.00001, but lower than the BS1 threshold of >0.0004, so neither criterion is met. This variant is rare and has been reported in at least 4 apparently unrelated probands affected with long QT syndrome 1 (PS4_Moderate; PMID:15840476, PMID:19716085, PMID:22949429, PMID:24606995, PMID:20851114). The variant has been reported to segregate with long QT syndrome 1 through a proband and 1 affected family member (PMID:26743238), which is not sufficient to meet PP1. This variant has been observed in 1 patient with an alternate molecular basis for disease (NM_000335.5(SCN5A):c.1231G>A (p.Val411Met)) with a phenotype that matches long QT syndrome 3 (BP5; PMID:28588847, PMID:23098067). This variant has also been observed in 1 patient with additional variants in KCNQ1 present both in cis (NM_000218.3(KCNQ1):c.502G>A (p.Gly168Arg)) and in trans (listed as p.Asp454Thrfs*7) providing an alternate molecular basis for disease (PMID:24667783), however, BP5 is only applicable when the phenotypes match another form of 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 0.01 for donor gain, which is lower than the ClinGen Potassium Channel Arrhythmia VCEP PP3 threshold of >0.5 and does not strongly predict a damaging effect on KCNQ1 splicing. The Meiler Lab functional impact predictor (http://servers.meilerlab.org/servers/show?s_id=29) was unable to generate a prediction of functional impact for this variant due to a limitation of the model and the unavailability of secondary structure at this residue (PMID:29021305), so neither PS3_Supporting nor BS3_Supporting was 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: PS4_Moderate, BP5. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA006724/MONDO:0100316/112

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:11 B:2 O:1
• Conservation: PhyloP100: 1.34
• Publications: 12 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: G2P, Labcorp Genetics (formerly Invitae)
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• BP5: 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.217C>A	p.Pro73Thr	missense	Exon 1 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.217C>A	p.Pro73Thr	missense	Exon 1 of 15	NP_001393765.1
	KCNQ1	NM_001406838.1		c.217C>A	p.Pro73Thr	missense	Exon 1 of 11	NP_001393767.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.217C>A	p.Pro73Thr	missense	Exon 1 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000910997.1		c.217C>A	p.Pro73Thr	missense	Exon 1 of 16	ENSP00000581056.1
	KCNQ1	ENST00000713725.1		c.217C>A	p.Pro73Thr	missense	Exon 1 of 15	ENSP00000519029.1	A0AAQ5BGS5

Frequencies

GnomAD3 genomes AF: 0.0000859 AC: 13 AN: 151300 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000658

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000153 AC: 23 AN: 150334 AF XY: 0.000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000426

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000275

Gnomad OTH exome AF: 0.000813

GnomAD4 exome AF: 0.000215 AC: 291 AN: 1353216 Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 141 AN XY: 671114

African (AFR) AF: 0.0000349 AC: 1 AN: 28668

American (AMR) AF: 0.0000573 AC: 2 AN: 34916

Ashkenazi Jewish (ASJ) AF: 0.0000427 AC: 1 AN: 23400

East Asian (EAS) AF: 0.00 AC: 0 AN: 33146

South Asian (SAS) AF: 0.00 AC: 0 AN: 74204

European-Finnish (FIN) AF: 0.0000300 AC: 1 AN: 33312

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4786

European-Non Finnish (NFE) AF: 0.000260 AC: 277 AN: 1065168

Other (OTH) AF: 0.000162 AC: 9 AN: 55616

GnomAD4 genome AF: 0.0000859 AC: 13 AN: 151300 Hom.: 0 Cov.: 32 AF XY: 0.0000541 AC XY: 4 AN XY: 73910

African (AFR) AF: 0.0000484 AC: 2 AN: 41310

American (AMR) AF: 0.0000658 AC: 1 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 67820

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000945

ExAC AF: 0.000117 AC: 13

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	1	1	Cardiovascular phenotype (2)
-	2	-	Long QT syndrome 1 (2)
-	1	-	Beckwith-Wiedemann syndrome;C1837014:Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)
-	1	-	Long QT syndrome (1)
-	-	1	not specified (1)
-	1	-	Short QT syndrome type 2 (1)
-	-	-	Congenital long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
CardioboostArm	Benign	0.012
BayesDel_addAF	Benign	0.0080	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	7.3
DANN	Benign	0.81
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.40	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.57
Sift	Benign	0.037	D
Sift4G	Benign	0.56	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.75		Gain of phosphorylation at P73 (P = 0.0102)
MVP		0.80
MPC		1.3
ClinPred		0.036	T
GERP RS		-0.73
PromoterAI		0.052	Neutral
Varity_R		0.033
gMVP		0.22
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs199472676; hg19: chr11-2466545;