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: 49 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.

Our verdict: Pathogenic. The variant received 17 points.

• PS3: 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).
• PM1: 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).
• PM2: 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.
• PM5: 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)
• PP3: Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — strong evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Strong).
• PP5: 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	NP_000209.2
	KCNQ1	NM_001406836.1		c.805G>A	p.Gly269Ser	missense	Exon 6 of 15	NP_001393765.1
	KCNQ1	NM_001406837.1		c.535G>A	p.Gly179Ser	missense	Exon 7 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.805G>A	p.Gly269Ser	missense	Exon 6 of 16	ENSP00000155840.2	P51787-1
	KCNQ1	ENST00000335475.6	TSL:1	c.424G>A	p.Gly142Ser	missense	Exon 6 of 16	ENSP00000334497.5	P51787-2
	KCNQ1	ENST00000910997.1		c.802G>A	p.Gly268Ser	missense	Exon 6 of 16	ENSP00000581056.1	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	0.00000657	1	0	152238	33
GnomAD2 exomes	0.00000399	1		250528
GnomAD4 exome	0.0000198	29	0	1461454	32
GnomAD4 genome Warning	0.00000656	1	0	152356	33
TOPMed (Bravo)	0.00000378
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.0000185	4	0	216362
Local & regional cohorts 2 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.000427	1	0	2342
ToMMo 61KJPN (+60KJPN MNV)	0.0000160	2	0	122504

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

Showing 29 of 29 scores

Splicing Scores

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

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.

Other links and lift over

dbSNP: rs120074193;

hg19: chr11-2594100;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar