NM_000218.3:c.1615C>T

Variant names:

• chr11-2775984-C-T
• rs199472795
• NM_000218.3:c.1615C>T
• KCNQ1 p.Arg539Trp

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.1615C>T (p.Arg539Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000657 (AC=1) in the gnomAD database across 152,192 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. 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. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000074019: Experimental studies have shown that this missense change affects KCNQ1 function (PMID:10728423, 15746441, 16556866, 21576493, 24681627, 25559286)." 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.R539Q: Pathogenic/Likely_pathogenic (ClinVar VariationId 67042, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13 O:1
• Conservation: PhyloP100: 1.69
• 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 18 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000074019: Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 10728423, 15746441, 16556866, 21576493, 24681627, 25559286).; SCV000919559: Multiple functional studies, Chouabe_2000 and Yamashita_2001, indicate the variant has a dominant-negative effect.; SCV005426371: Functional studies have shown that this variant leads to a reduction in PIP2 binding affinity, resulting in a decreased current amplitude of the potassium channel (PMID: 10728423, 15746441, 21576493, 23251633, 25234465).; SCV000280148: Functional studies show that this variant causes a positive voltage shift of channel activation (Chouabe et al 2000) and weaker stabilization of the open state of the potassium channel, decreasing the maximal current (Peroz et al 2008).; SCV002703185: Furthermore, functional studies have reported this alteration to result in abnormal ion channel function (Park KH et al. Circ Res. 2005;96(7):730-9; Peroz D et al. J Physiol (Lond). 2008;586(7):1785-9; Coyan FC et al. PLoS ONE. 2014;9(3):e93255).; SCV005366160: "In vitro functional studies have demonstrated that this variant negatively impacts potassium channel function (Chouabe et al. 2000. PubMed ID: 10728423; Park et al. 2005. PubMed ID: 15746441; Coyan et al. 2014. PubMed ID: 24681627)."
	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: 5 pathogenic, 0 benign (OR vs. background: 55.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000147 — very rare for AD+AR gene (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.R539Q: Pathogenic/Likely_pathogenic (ClinVar VariationId 67042, 2 stars)
	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 (13/13 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.1615C>T p.Arg539Trp	missense	Exon 13 of 16	Prot: NP_000209.2
	KCNQ1 NM_001406836.1		c.1519C>T p.Arg507Trp	missense	Exon 12 of 15	Prot: NP_001393765.1
	KCNQ1 NM_001406837.1		c.1345C>T p.Arg449Trp	missense	Exon 14 of 17	Prot: NP_001393766.1

KCNQ1 NM_000218.3

MANE Select

HGVSc / HGVSpc.1615C>Tp.Arg539Trp

Exon rankExon 13 of 16

missense

Prot: NP_000209.2

KCNQ1 NM_001406836.1

HGVSc / HGVSpc.1519C>Tp.Arg507Trp

Exon rankExon 12 of 15

missense

Prot: NP_001393765.1

KCNQ1 NM_001406837.1

HGVSc / HGVSpc.1345C>Tp.Arg449Trp

Exon rankExon 14 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.1615C>T p.Arg539Trp	missense	Exon 13 of 16	Prot: ENSP00000155840.2 UniProt:
	KCNQ1 ENST00000335475.6	TSL:1	c.1234C>T p.Arg412Trp	missense	Exon 13 of 16	Prot: ENSP00000334497.5 UniProt:
	KCNQ1 ENST00000910997.1		c.1612C>T p.Arg538Trp	missense	Exon 13 of 16	Prot: ENSP00000581056.1 UniProt:

KCNQ1 ENST00000155840.12

TSL:1MANE Select

HGVSc / HGVSpc.1615C>Tp.Arg539Trp

Exon rankExon 13 of 16

missense

Prot: ENSP00000155840.2UniProt: P51787-1

KCNQ1 ENST00000335475.6

TSL:1

HGVSc / HGVSpc.1234C>Tp.Arg412Trp

Exon rankExon 13 of 16

missense

Prot: ENSP00000334497.5UniProt: P51787-2

KCNQ1 ENST00000910997.1

HGVSc / HGVSpc.1612C>Tp.Arg538Trp

Exon rankExon 13 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:152192	Cov:33
GnomAD2 exomes	AF: 0.00000553	AC:1	Hom:	AN:180864	Cov:
GnomAD4 exome Warning	AF: 0.00000283	AC:4	Hom:0	AN:1415590	Cov:31
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152192	Cov:33
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00000481	AC:1	Hom:0	AN:207788	Cov:

Showing 6 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Long QT syndrome (4)
3	-	-	Long QT syndrome 1 (3)
3	-	-	not provided (3)
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	-	-	Cardiovascular phenotype (1)
1	-	-	KCNQ1-related disorder (1)
-	-	-	Congenital long QT syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	30
CardioboostArm	Pathogenic	1.0
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.83	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-9.6
GPN-Star score	N/A	9.6
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.5	M
PhyloP100	Benign	1.7
popEVE	Benign	-3.6
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.75
VESM-3B	Benign	-13

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	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: rs199472795;

hg19: chr11-2797214;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar