chr11-2778003-C-T

Variant names:

• chr11-2778003-C-T
• rs120074189
• NM_000218.3:c.1760C>T
• KCNQ1 p.Thr587Met

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 16 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_ModeratePP5_Strong

The NM_000218.3(KCNQ1):c.1760C>T (p.Thr587Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,444 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. 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: "SCV000074039: Experimental studies have shown that this missense change affects KCNQ1 function (PMID:11162126, 19959132, 20348026)." 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.T587R: Likely_pathogenic (ClinVar VariationId 1037124, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T587= (synonymous): Likely_benign (ClinVar VariationId 413282, 2 stars) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Jervell and lange-nielsen syndrome 1 (jlns1).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNQ1 NM_000218.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 3.41
• Publications: 27 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 16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000074039: Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 11162126, 19959132, 20348026).; SCV000234524: "Furthermore, in vivo functional analyses showed that, in the presence of the T587M variant, protein trafficking was adversely affected (Yamashita et al., 2001; Biliczki et al., 2009; Hayashi et al., 2010)."; SCV000737556: "In vitro studies have reported this alteration to result in non-functional channels (Yamashita F et al. J Mol Cell Cardiol. 2001;33(2):197-207; Biliczki P et al. Heart Rhythm. 2009; 6(12):1792-801)."; SCV005362431: Functional studies suggest this variant compromises the structure and function of Kv7 potassium ion channels, which are important in cardiac and other tissues (Howard et al. 2007. PubMed ID: 17329207).
	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: 14 pathogenic, 0 benign (OR vs. background: 145.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — 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.T587R: Likely_pathogenic (ClinVar VariationId 1037124, 1 star); Other variants at the same amino acid residue (not pathogenic): p.T587= (synonymous): Likely_benign (ClinVar VariationId 413282, 2 stars)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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.1760C>T p.Thr587Met	missense	Exon 15 of 16	Prot: NP_000209.2
	KCNQ1 NM_001406836.1		c.1664C>T p.Thr555Met	missense	Exon 14 of 15	Prot: NP_001393765.1
	KCNQ1 NM_001406837.1		c.1490C>T p.Thr497Met	missense	Exon 16 of 17	Prot: NP_001393766.1

KCNQ1 NM_000218.3

MANE Select

HGVSc / HGVSpc.1760C>Tp.Thr587Met

Exon rankExon 15 of 16

missense

Prot: NP_000209.2

KCNQ1 NM_001406836.1

HGVSc / HGVSpc.1664C>Tp.Thr555Met

Exon rankExon 14 of 15

missense

Prot: NP_001393765.1

KCNQ1 NM_001406837.1

HGVSc / HGVSpc.1490C>Tp.Thr497Met

Exon rankExon 16 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.1760C>T p.Thr587Met	missense	Exon 15 of 16	Prot: ENSP00000155840.2 UniProt:
	KCNQ1 ENST00000335475.6	TSL:1	c.1379C>T p.Thr460Met	missense	Exon 15 of 16	Prot: ENSP00000334497.5 UniProt:
	KCNQ1 ENST00000910997.1		c.1757C>T p.Thr586Met	missense	Exon 15 of 16	Prot: ENSP00000581056.1 UniProt:

KCNQ1 ENST00000155840.12

TSL:1MANE Select

HGVSc / HGVSpc.1760C>Tp.Thr587Met

Exon rankExon 15 of 16

missense

Prot: ENSP00000155840.2UniProt: P51787-1

KCNQ1 ENST00000335475.6

TSL:1

HGVSc / HGVSpc.1379C>Tp.Thr460Met

Exon rankExon 15 of 16

missense

Prot: ENSP00000334497.5UniProt: P51787-2

KCNQ1 ENST00000910997.1

HGVSc / HGVSpc.1757C>Tp.Thr586Met

Exon rankExon 15 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: 6.84e-7	AC:1	Hom:0	AN:1461444	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:204044	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122380	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Long QT syndrome (2)
2	-	-	not provided (2)
1	-	-	Cardiovascular phenotype (1)
1	-	-	Jervell and Lange-Nielsen syndrome 1 (1)
1	-	-	KCNQ1-related disorder (1)
1	-	-	Long QT syndrome 1 (1)
-	-	-	Congenital long QT syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	22
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.42
CADD	Uncertain	23
CardioboostArm	Pathogenic	1.0
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.89	D
FuncVEP CTI	Pathogenic	0.97
GPN-Star LLR	N/A	-7.2
GPN-Star score	N/A	7.2
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
Mutation Taster	N/A	5/95	disease causing (ClinVar)
MutationAssessor	Uncertain	2.5	M
PhyloP100	Benign	3.4
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.54	T
PromoterAI	N/A	0.049	Neutral
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.83
Sift	Benign	0.082	T
Sift4G	Benign	0.19	T
Varity_R	N/A	0.21
VESM-3B	Benign	-8.4

Showing 30 of 30 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
Splicevardb	N/A	2.0

Showing 3 of 3 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: rs120074189;

hg19: chr11-2799233;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar