Genetic Variant NM_000218.3:c.1085A>G (chr11-2585264-A-G) – ACMG Classification: Pathogenic (17 pts)

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3PM1PP2PP3_ModeratePP5_Very_Strong

The NM_000218.3(KCNQ1):c.1085A>G(p.Lys362Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000626 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000073970: Experimental studies have shown that this missense change affects KCNQ1 function (PMID:24947509, 26546361)." and additional evidence is available in ClinVar. The gene KCNQ1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

KCNQ1
NM_000218.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 8.70

Publications

18 publications found

Variant links:

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
long QT syndrome 1
Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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)
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: Labcorp Genetics (formerly Invitae), G2P
familial atrial fibrillation
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Jervell and Lange-Nielsen syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

KCNQ1 links:

Genome browser will be placed here

ACMG classification

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 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000073970: Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 24947509, 26546361).; SCV001372408: At least one publication reports experimental evidence evaluating an impact on protein function and suggests the variant may impact channel function (Slaats_2015).; SCV004838825: "In vitro functional studies have shown that this variant affects current amplitude in vitro and disrupts the potassium channel regulation in renal ciliogenesis." PMID:24947509, 26546361; SCV000966929: "In vitro functional studies provide some evidence that the p.Lys362Arg variant may impact the protein." PMID:26546361, PMID:24947509; SCV004101338: A functional study conducted in non-human cells demonstrated that this variant impacts protein function (PMID: 26546361).; SCV005399145: Functional studies have demonstrated that this variant directly interacts with membrane lipid phosphatidylinositol 4,5-bisphosphate (PIP2), which is required for Kv7 channel opening. However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification (PMID: 24947509).; SCV001344629: Functional studies have shown that this variant affects the potassium channel function (PMID: 24947509, 26546361).; SCV004046379: Experimental studies have shown that the presence of this variant leads to an abnormal KCNQ1 channel (PMID: 24947509, 26546361).; SCV003925210: Functional studies have shown that this missense variant affects the potassium channel regulation in renal ciliogenesis and that is involved in anionic phospholipids binding. However, these studies are not conclusive regarding the potential effect of this variant on the cardiac ion channel [PMID: 21084310, 24947509, 26546361].; SCV006555833: Functional studies show a shift in the voltage dependence of channel activation toward depolarization potentials, a reduction in current density, and disrupts phosphoinositide binding, indicating that this variant impacts protein function (Slaats GG et al., PMID: 36546361).

PM1

In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000218.3

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 212 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 1.8321 (below the threshold of 3.09). Trascript score misZ: 0.90233 (below the threshold of 3.09). GenCC associations: The gene is linked to short QT syndrome, Jervell and Lange-Nielsen syndrome 1, long QT syndrome 1, familial atrial fibrillation, short QT syndrome type 2, long QT syndrome, atrial fibrillation, familial, 3, Jervell and Lange-Nielsen syndrome, hypertrophic cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.924

PP5

Variant 11-2585264-A-G is Pathogenic according to our data. Variant chr11-2585264-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 52953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000218.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ1	NM_000218.3	MANE Select	c.1085A>G	p.Lys362Arg	missense	Exon 8 of 16	NP_000209.2
KCNQ1	NM_001406837.1		c.815A>G	p.Lys272Arg	missense	Exon 9 of 17	NP_001393766.1
KCNQ1	NM_181798.2		c.704A>G	p.Lys235Arg	missense	Exon 8 of 16	NP_861463.1	P51787-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KCNQ1	ENST00000155840.12	TSL:1 MANE Select	c.1085A>G	p.Lys362Arg	missense	Exon 8 of 16	ENSP00000155840.2	P51787-1
KCNQ1	ENST00000335475.6	TSL:1	c.704A>G	p.Lys235Arg	missense	Exon 8 of 16	ENSP00000334497.5	P51787-2
KCNQ1	ENST00000910997.1		c.1082A>G	p.Lys361Arg	missense	Exon 8 of 16	ENSP00000581056.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251350

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000677

AC:

AN:

1461718

Hom.:

Cov.:

AF XY:

0.0000509

AC XY:

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000854

AC:

AN:

1111986

Other (OTH)

AF:

0.0000331

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000101

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Long QT syndrome 1 (5)

Long QT syndrome (3)

Cardiovascular phenotype (2)

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551509:Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)

Atrial fibrillation, familial, 3;C1865019:Short QT syndrome type 2;C4551647:Long QT syndrome 1 (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)

Cardiac arrhythmia (1)

Congenital long QT syndrome (2)

Jervell and Lange-Nielsen syndrome 1;C4551647:Long QT syndrome 1 (1)

KCNQ1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.92

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

2.9

PhyloP100

8.7

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.86

MVP

0.98

MPC

1.0

ClinPred

0.94

GERP RS

3.8

Varity_R

0.89

gMVP

0.86

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over