chr11-2583453-G-A

Variant names:

• chr11-2583453-G-A
• rs120074184
• NM_000218.3:c.940G>A
• KCNQ1 p.Gly314Ser

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 18 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_StrongPP5_Strong

The NM_000218.3(KCNQ1):c.940G>A (p.Gly314Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: 9.36). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV005399369: "Moderate functional evidence supporting abnormal protein function. Patch clamp analysis indicates that this variant reduces channel current in a dominant negative manner (PMID:19348785)."" 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.G314R: Pathogenic/Likely_pathogenic (ClinVar VariationId 53136, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G314A: not_provided (ClinVar VariationId 67126); p.G314C: not_provided (ClinVar VariationId 53137); p.G314= (synonymous): Likely_benign (ClinVar VariationId 4614417, 1 star); p.G314= (synonymous): Likely_benign (ClinVar VariationId 4614419, 1 star); p.G314= (synonymous): Likely_benign (ClinVar VariationId 4614420, 1 star) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Long qt syndrome 1 (lqt1); it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11 O:1
• Conservation: PhyloP100: 9.36
• Publications: 33 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 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV005399369: "Moderate functional evidence supporting abnormal protein function. Patch clamp analysis indicates that this variant reduces channel current in a dominant negative manner (PMID: 19348785)."; SCV000234440: Published functional studies demonstrate a damaging effect as it failed to produce functional homomeric channels, and reduced the K+ current when co-expressed with the wild-type subunit (PMID: 30571187, 9312006); SCV005877880: Functional analyses of the variant protein show significantly reduced current density (Chouabe 1997, Westenskow 2004). PMID: 9312006. PMID: 15051636.; SCV001592372: Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 9312006, 15051636, 19348785).; SCV002686454: "In assays testing KCNQ1 function, this variant showed a functionally abnormal result (Chouabe C et al. EMBO J. 1997;16:5472-9; Westenskow P et al. Circulation. 2004;109:1834-41)."
	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: 32 pathogenic, 0 benign (OR vs. background: 325.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.00022 by highest known P/LP ClinVar AF 0.00022) — PM2 moderate.
	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.G314R: Pathogenic/Likely_pathogenic (ClinVar VariationId 53136, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.G314A: not_provided (ClinVar VariationId 67126); p.G314C: not_provided (ClinVar VariationId 53137); p.G314= (synonymous): Likely_benign (ClinVar VariationId 4614417, 1 star); p.G314= (synonymous): Likely_benign (ClinVar VariationId 4614419, 1 star); p.G314= (synonymous): Likely_benign (ClinVar VariationId 4614420, 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 (11/11 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.940G>A p.Gly314Ser	missense	Exon 7 of 16	Prot: NP_000209.2
	KCNQ1 NM_001406836.1		c.940G>A p.Gly314Ser	missense	Exon 7 of 15	Prot: NP_001393765.1
	KCNQ1 NM_001406837.1		c.670G>A p.Gly224Ser	missense	Exon 8 of 17	Prot: NP_001393766.1

KCNQ1 NM_000218.3

MANE Select

HGVSc / HGVSpc.940G>Ap.Gly314Ser

Exon rankExon 7 of 16

missense

Prot: NP_000209.2

KCNQ1 NM_001406836.1

HGVSc / HGVSpc.940G>Ap.Gly314Ser

Exon rankExon 7 of 15

missense

Prot: NP_001393765.1

KCNQ1 NM_001406837.1

HGVSc / HGVSpc.670G>Ap.Gly224Ser

Exon rankExon 8 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.940G>A p.Gly314Ser	missense	Exon 7 of 16	Prot: ENSP00000155840.2 UniProt:
	KCNQ1 ENST00000335475.6	TSL:1	c.559G>A p.Gly187Ser	missense	Exon 7 of 16	Prot: ENSP00000334497.5 UniProt:
	KCNQ1 ENST00000910997.1		c.937G>A p.Gly313Ser	missense	Exon 7 of 16	Prot: ENSP00000581056.1 UniProt:

KCNQ1 ENST00000155840.12

TSL:1MANE Select

HGVSc / HGVSpc.940G>Ap.Gly314Ser

Exon rankExon 7 of 16

missense

Prot: ENSP00000155840.2UniProt: P51787-1

KCNQ1 ENST00000335475.6

TSL:1

HGVSc / HGVSpc.559G>Ap.Gly187Ser

Exon rankExon 7 of 16

missense

Prot: ENSP00000334497.5UniProt: P51787-2

KCNQ1 ENST00000910997.1

HGVSc / HGVSpc.937G>Ap.Gly313Ser

Exon rankExon 7 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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:191178	Cov:

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Long QT syndrome 1 (5)
3	-	-	Long QT syndrome (3)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
-	-	-	Congenital long QT syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
CardioboostArm	Pathogenic	1.0
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.84	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-9.6
GPN-Star score	N/A	9.6
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.89	D
Mutation Taster	N/A	1/99	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.8	H
PhyloP100	Pathogenic	9.4
popEVE	Benign	-4.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Varity_R	N/A	0.97
VESM-3B	Benign	-14

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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.

2 no calibration

2 assays found for this variant.

No calibration: 2 assays (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Protein level

Normalized currents of 62 KCNQ1 missense SNVs in the homozygous state.

Proactive functional classification of all possible missense single-nucleotide variants in KCNQ4

• Gene: KCNQ1
• Assay type: Direct protein function
• Mechanism: Gain or loss of function
• Model system: Other (Cricetulus griseus)
• Score: 0.00457 · p.Gly314Ser (assay numbering)

No calibration data

This score is at approximately the 32th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

Normalized currents of 62 KCNQ1 missense SNVs in the homozygous state

Proactive functional classification of all possible missense single-nucleotide variants in KCNQ4

• Gene: KCNQ1
• Assay type: Direct protein function
• Mechanism: Gain or loss of function
• Model system: Other (Cricetulus griseus)
• Score: 0.00457 · p.Gly314Ser (assay numbering)

No calibration data

This score is at approximately the 32th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs120074184;

hg19: chr11-2604683;

COSMIC: COSV108030945;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar