rs199472694

Variant names:

• chr11-2570664-G-A
• rs199472694
• NM_000218.3:c.514G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-2570664-G-A
• chr11-2570664-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS3_Supporting BS1 BS4

This summary comes from the ClinGen Evidence Repository: NM_000218.3(KCNQ1):c.514G>A is a missense variant that substitutes valine with methionine at codon 172 (p.Val172Met). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001317, with 12 alleles / 91,084 total alleles in the South Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0001 (BS1). At least two patients affected with long QT syndrome have been identified with the p.Val172Met and p.Arg293Cys variants in cis, in the homozygous state (PMID:28944242, PMID:28438721). However, PM3 is not met because the variant is not sufficiently rare. The variant has been observed in a family with long QT syndrome but fails to segregate with the disease phenotype in at least 2 affected members (PMID:28438721; BS4). This variant has been observed in at least 2 probands with a possible alternate molecular basis for disease, however, the alternative variants are located within KCNQ1 itself and the phenotype does not match another form of LQTS, so this evidence is not considered eligible for the BP5 code (PMID:28944242, PMID:28438721). Exogenously expressed KCNQ1 harboring this variant has an IKs of 1.117 (expressed as a fraction of the wild-type), which indicates higher-than-wild-type activity within the near-normal range (PMID:30571187). The Meiler Lab functional impact predictor gave this variant a classification of normal for IKs, V1/2_classification, Tau of activation, and Tau of deactviation, consistent with benign impact on the protein product (PMID:29021305, BS3_Moderate). 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 Arrhythmia VCEP: BS1, BS4, and BS3_Moderate. (VCEP specifications version 1.0.0; date of approval 03/04/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA007311/MONDO:0100316/112

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Benign reviewed by expert panel U:10 B:3 O:1
• Conservation: PhyloP100: 2.94
• Publications: 8 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: Benign. The variant received -9 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.
• BS4: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	NM_000218.3	MANE Select	c.514G>A	p.Val172Met	missense	Exon 3 of 16	NP_000209.2
	KCNQ1	NM_001406836.1		c.514G>A	p.Val172Met	missense	Exon 3 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.244G>A	p.Val82Met	missense	Exon 4 of 17	NP_001393766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.514G>A	p.Val172Met	missense	Exon 3 of 16	ENSP00000155840.2
	KCNQ1	ENST00000335475.6	TSL:1	c.133G>A	p.Val45Met	missense	Exon 3 of 16	ENSP00000334497.5
	KCNQ1	ENST00000713725.1		c.514G>A	p.Val172Met	missense	Exon 3 of 15	ENSP00000519029.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000521 AC: 13 AN: 249562 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000336 AC: 49 AN: 1460330 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 726558

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51946

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111966

Other (OTH) AF: 0.0000662 AC: 4 AN: 60384

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.0000241 AC: 1 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:10 Benign:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3

Jan 29, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 11, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Observed on the same allele (in cis) with p.(R293C) in unrelated patients at GeneDx; This variant is associated with the following publications: (PMID: 27650965, 14678125, 26077850, 27159321, 27884173, 28944242, 30919684, 34426522, 34505893, 35463915, 22581653, 31737537, 31751626, 19716085, 29197658, 28438721)

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KCNQ1: PM1, PM2:Supporting

Long QT syndrome 1 Uncertain:1 Benign:1

Jul 01, 2025

ClinGen Potassium Channel Arrhythmia Variant Curation Expert Panel, ClinGen

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

NM_000218.3(KCNQ1):c.514G>A is a missense variant that substitutes valine with methionine at codon 172 (p.Val172Met). This variant is present in gnomAD v.4.1.0 at a maximum allele frequency of 0.0001317, with 12 alleles / 91,084 total alleles in the South Asian population, which is higher than the ClinGen Potassium Channel Arrhythmia VCEP BS1 threshold of >0.0001 (BS1). At least two patients affected with long QT syndrome have been identified with the p.Val172Met and p.Arg293Cys variants in cis, in the homozygous state (PMID: 28944242, PMID: 28438721). However, PM3 is not met because the variant is not sufficiently rare. The variant has been observed in a family with long QT syndrome but fails to segregate with the disease phenotype in at least 2 affected members (PMID: 28438721; BS4). This variant has been observed in at least 2 probands with a possible alternate molecular basis for disease, however, the alternative variants are located within KCNQ1 itself and the phenotype does not match another form of LQTS, so this evidence is not considered eligible for the BP5 code (PMID: 28944242, PMID: 28438721). Exogenously expressed KCNQ1 harboring this variant has an IKs of 1.117 (expressed as a fraction of the wild-type), which indicates higher-than-wild-type activity within the near-normal range (PMID: 30571187). The Meiler Lab functional impact predictor gave this variant a classification of normal for IKs, V1/2_classification, Tau of activation, and Tau of deactviation, consistent with benign impact on the protein product (PMID: 29021305, BS3_Moderate). 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 Arrhythmia VCEP: BS1, BS4, and BS3_Moderate. (VCEP specifications version 1.0.0; date of approval 03/04/2025).

May 16, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not specified Uncertain:1

Feb 11, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Atrial fibrillation, familial, 3 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jervell and Lange-Nielsen syndrome 1 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Long QT syndrome Uncertain:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 172 of the KCNQ1 protein (p.Val172Met). This variant is present in population databases (rs199472694, gnomAD 0.02%). This missense change has been observed in individual(s) with long QT syndrome (PMID: 14678125, 27650965, 28944242, 31737537, 34505893). ClinVar contains an entry for this variant (Variation ID: 67078). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Cardiovascular phenotype Uncertain:1

Mar 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.514G>A (p.V172M) 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 514, causing the valine (V) at amino acid position 172 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Short QT syndrome type 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.

Cardiac arrhythmia Benign:1

Sep 21, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:14678125;PMID:19716085). 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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
CardioboostArm	Benign	0.00045
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.35
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	0.92	L
PhyloP100		2.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.4	N
REVEL	Pathogenic	0.71
Sift	Benign	0.052	T
Sift4G	Benign	0.083	T
Polyphen		0.80	P
Vest4		0.58
MutPred		0.85		Gain of MoRF binding (P = 0.1138)
MVP		0.95
MPC		0.59
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.22
gMVP		0.86
Mutation Taster		=13/87	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: rs199472694; hg19: chr11-2591894; COSMIC: COSV50116050;