chr11-2583453-GGC-TCA

Variant names:

• chr11-2583453-GGC-TCA
• NM_000218.3:c.940_942delGGCinsTCA
• KCNQ1 p.Gly314Ser

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_ModerateO7_SupportingO8_Supporting

The NM_000218.3(KCNQ1):c.940_942delGGCinsTCA (p.Gly314Ser) variant causes a missense change. The gene KCNQ1 is a tumor suppressor gene (CancerMine: 11 TSG, 2 oncogene citations). The gene KCNQ1 is a known oncogene (CancerMine: 11 TSG, 2 oncogene citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.36). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to 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: Not reported in ClinVar
• Conservation: PhyloP100: 9.36
• Publications: 0 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 ACGS-UK Somatic Oncogenicity v2025

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: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: true | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 32 pathogenic, 0 benign (OR vs. background: 325.0); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.91 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

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.940_942delGGCinsTCA p.Gly314Ser	missense	N/A	Prot: NP_000209.2
	KCNQ1 NM_001406836.1		c.940_942delGGCinsTCA p.Gly314Ser	missense	N/A	Prot: NP_001393765.1
	KCNQ1 NM_001406837.1		c.670_672delGGCinsTCA p.Gly224Ser	missense	N/A	Prot: NP_001393766.1

KCNQ1 NM_000218.3

MANE Select

HGVSc / HGVSpc.940_942delGGCinsTCAp.Gly314Ser

Exon rankN/A

missense

Prot: NP_000209.2

KCNQ1 NM_001406836.1

HGVSc / HGVSpc.940_942delGGCinsTCAp.Gly314Ser

Exon rankN/A

missense

Prot: NP_001393765.1

KCNQ1 NM_001406837.1

HGVSc / HGVSpc.670_672delGGCinsTCAp.Gly224Ser

Exon rankN/A

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.940_942delGGCinsTCA p.Gly314Ser	missense	N/A	Prot: ENSP00000155840.2 UniProt:
	KCNQ1 ENST00000335475.6	TSL:1	c.559_561delGGCinsTCA p.Gly187Ser	missense	N/A	Prot: ENSP00000334497.5 UniProt:
	KCNQ1 ENST00000910997.1		c.937_939delGGCinsTCA p.Gly313Ser	missense	N/A	Prot: ENSP00000581056.1 UniProt:

KCNQ1 ENST00000155840.12

TSL:1MANE Select

HGVSc / HGVSpc.940_942delGGCinsTCAp.Gly314Ser

Exon rankN/A

missense

Prot: ENSP00000155840.2UniProt: P51787-1

KCNQ1 ENST00000335475.6

TSL:1

HGVSc / HGVSpc.559_561delGGCinsTCAp.Gly187Ser

Exon rankN/A

missense

Prot: ENSP00000334497.5UniProt: P51787-2

KCNQ1 ENST00000910997.1

HGVSc / HGVSpc.937_939delGGCinsTCAp.Gly313Ser

Exon rankN/A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.4

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr11-2604683;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar