chr11-2572870-G-A

Variant names:

• chr11-2572870-G-A
• rs120074193
• NM_000218.3:c.805G>A
• KCNQ1 p.Gly269Ser

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 17 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_StrongPP5_Strong

The NM_000218.3(KCNQ1):c.805G>A (p.Gly269Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000198 (AC=29) in the gnomAD database across 1,461,454 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000653. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.42). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005399103: "This variant has moderate functional evidence supporting abnormal protein function. In vitro studies show that this variant has abnormal delayed rectifier potassium current, defects in subcellular localisation, reduced stability, and a dominant negative effect over wild type (PMID:20044973, 24184248)."" and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.G269V: Pathogenic (ClinVar VariationId 200899, 1 star) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Long qt syndrome 1 (lqt1).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 9.42
• 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
• 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)
• long QT syndrome 1

  Inheritance: AR, AD 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: G2P, Labcorp Genetics (formerly Invitae)
• familial atrial fibrillation

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

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

  Inheritance: AD Classification: NO_KNOWN Submitted by: G2P
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

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

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005399103: "This variant has moderate functional evidence supporting abnormal protein function. In vitro studies show that this variant has abnormal delayed rectifier potassium current, defects in subcellular localisation, reduced stability, and a dominant negative effect over wild type (PMID: 20044973, 24184248)."; SCV005440608: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000234421: Published functional studies demonstrate a damaging effect as this variant may cause abnormal assembly and stability of the potassium channel and exert moderate dominant-negative suppression of the potassium channel (Verma et al., 2009; Wu et al., 2014; Wang et al., 2014); SCV000543295: Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 20044973, 24184248).; SCV005426308: A functional study has shown that this variant leads to a modest reduction in potassium channel current under control conditions and results in a completely blunted channel response to PKA stimulation (PMID: 24184248).; SCV001160534: "functional studies demonstrate that the p.Gly269Ser variant causes a reduction in potassium ion current and protein stability (Wu 2014 and Verma 2010)."; SCV002675873: "In multiple assays testing KCNQ1 function, this variant showed functionally abnormal results (Murray A et al. J. Med. Genet., 2002 Sep;39:681-5; Wu J et al. J. Am. Coll. Cardiol., 2014 Mar;63:819-27)."; SCV006064784: A functional study has shown that this variant leads to a modest reduction in potassium channel current under control conditions and results in a completely blunted channel response to PKA stimulation (PMID: 24184248).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 23 pathogenic, 1 benign (OR vs. background: 78.3).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000653 — borderline rare for AD+AR gene (base 0.0001, raised to 0.00022 by highest known P/LP ClinVar AF 0.00022) — PM2 supporting.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.G269V: Pathogenic (ClinVar VariationId 200899, 1 star)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s). ClinVar submissions strongly and reliably favor pathogenicity (14/14 total P/LP).

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNQ1 NM_000218.3	MANE Select	c.805G>A p.Gly269Ser	missense	Exon 6 of 16	Prot: NP_000209.2
	KCNQ1 NM_001406836.1		c.805G>A p.Gly269Ser	missense	Exon 6 of 15	Prot: NP_001393765.1
	KCNQ1 NM_001406837.1		c.535G>A p.Gly179Ser	missense	Exon 7 of 17	Prot: NP_001393766.1

KCNQ1 NM_000218.3

MANE Select

HGVSc / HGVSpc.805G>Ap.Gly269Ser

Exon rankExon 6 of 16

missense

Prot: NP_000209.2

KCNQ1 NM_001406836.1

HGVSc / HGVSpc.805G>Ap.Gly269Ser

Exon rankExon 6 of 15

missense

Prot: NP_001393765.1

KCNQ1 NM_001406837.1

HGVSc / HGVSpc.535G>Ap.Gly179Ser

Exon rankExon 7 of 17

missense

Prot: NP_001393766.1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	KCNQ1 ENST00000155840.12	TSL:1MANE Select	c.805G>A p.Gly269Ser	missense	Exon 6 of 16	Prot: ENSP00000155840.2 UniProt:
	KCNQ1 ENST00000335475.6	TSL:1	c.424G>A p.Gly142Ser	missense	Exon 6 of 16	Prot: ENSP00000334497.5 UniProt:
	KCNQ1 ENST00000910997.1		c.802G>A p.Gly268Ser	missense	Exon 6 of 16	Prot: ENSP00000581056.1 UniProt:

KCNQ1 ENST00000155840.12

TSL:1MANE Select

HGVSc / HGVSpc.805G>Ap.Gly269Ser

Exon rankExon 6 of 16

missense

Prot: ENSP00000155840.2UniProt: P51787-1

KCNQ1 ENST00000335475.6

TSL:1

HGVSc / HGVSpc.424G>Ap.Gly142Ser

Exon rankExon 6 of 16

missense

Prot: ENSP00000334497.5UniProt: P51787-2

KCNQ1 ENST00000910997.1

HGVSc / HGVSpc.802G>Ap.Gly268Ser

Exon rankExon 6 of 16

missense

Prot: ENSP00000581056.1UniProt: A0ACI8SIJ2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152238	Cov:33
GnomAD2 exomes	AF: 0.00000399	AC:1	Hom:	AN:250528	Cov:
GnomAD4 exome	AF: 0.0000198	AC:29	Hom:0	AN:1461454	Cov:32
GnomAD4 genome Warning	AF: 0.00000656	AC:1	Hom:0	AN:152356	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000185	AC:4	Hom:0	AN:216362	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122504	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.00	0	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.00000970	1	103044	0.0000163	3	184104

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	33
CardioboostArm	Pathogenic	1.0
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.97	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.8
GPN-Star score	N/A	9.8
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Benign	1.4	L
PhyloP100	Pathogenic	9.4
popEVE	Benign	-3.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.93
Sift	Benign	0.070	T
Sift4G	Benign	0.075	T
Varity_R	N/A	0.97
VESM-3B	Benign	-11

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.070	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs120074193;

hg19: chr11-2594100;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar