chr17-70175691-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000891.3(KCNJ2):c.652C>T(p.Arg218Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218Q) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNJ2
NM_000891.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13O:2

Conservation

PhyloP100: 2.19

Variant links:

Genes affected

KCNJ2 (HGNC:6263): (potassium inwardly rectifying channel subfamily J member 2) Potassium channels are present in most mammalian cells, where they participate in a wide range of physiologic responses. The protein encoded by this gene is an integral membrane protein and inward-rectifier type potassium channel. The encoded protein, which has a greater tendency to allow potassium to flow into a cell rather than out of a cell, probably participates in establishing action potential waveform and excitability of neuronal and muscle tissues. Mutations in this gene have been associated with Andersen syndrome, which is characterized by periodic paralysis, cardiac arrhythmias, and dysmorphic features. [provided by RefSeq, Jul 2008]

KCNJ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-70175692-G-A is described in Lovd as [Pathogenic].

PP2

Missense variant in the KCNJ2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 51 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 2.7459 (below the threshold of 3.09). Trascript score misZ: 3.9347 (above the threshold of 3.09). GenCC associations: The gene is linked to long QT syndrome, short QT syndrome, Andersen-Tawil syndrome, familial atrial fibrillation, short QT syndrome type 3, catecholaminergic polymorphic ventricular tachycardia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 17-70175691-C-T is Pathogenic according to our data. Variant chr17-70175691-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-70175691-C-T is described in Lovd as [Pathogenic]. Variant chr17-70175691-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNJ2	NM_000891.3 link	c.652C>T	p.Arg218Trp	missense_variant	Exon 2 of 2	ENST00000243457.4	NP_000882.1	P63252

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4 link	c.652C>T	p.Arg218Trp	missense_variant	Exon 2 of 2	1	NM_000891.3	ENSP00000243457.2		P63252
KCNJ2	ENST00000535240.1 link	c.652C>T	p.Arg218Trp	missense_variant	Exon 2 of 2	1		ENSP00000441848.1		P63252

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 04, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies demonstrate a damaging effect: the variant causes a loss of function and a dominant negative effect on channel function when expressed with the wild-type protein (Plaster et al., 2001; Lange et al. 2003; Caballero et al., 2010); Also known as Kir2.1; This variant is associated with the following publications: (PMID: 12163457, 17568571, 17211524, 23631430, 20647529, 11371347, 25415519, 23867365, 15269659, 17119796, 18554214, 28501311, 12796536, 17221872, 22589293, 29093808, 15852530, 16217063, 17399642, 22581653, 28024840, 31068157, 31567646, 34008892, 35460302, 33057326, 20713726, 12909315) -

May 10, 2018

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Andersen Tawil syndrome

Pathogenic:4Other:1

May 18, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 05, 2022

Center of Excellence for Medical Genomics, Chulalongkorn University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 18, 2018

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM5, PP2, PP3, PP4, PP5 -

Jan 06, 2020

Genetics Laboratory, Department of Biology, Semnan University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: case-control

The identified mutation leads to the substitution of Arginine 218 with Tryptophan (R218W) in the KCNJ2 protein. Hence, this substitution alters the amino acid sequence and leads to a missense mutation at position 218 with possible increased function in the mutated protein. -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3;C3151431:Atrial fibrillation, familial, 9

Pathogenic:1

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Moderate+PP2+PS4+PM6_Supporting+PP1_Strong -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3

Pathogenic:1

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 218 of the KCNJ2 protein (p.Arg218Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Andersen-Tawil syndrome (PMID: 12796536, 17119796, 17221872, 22589293). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8919). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt KCNJ2 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 12909315, 17119796, 17568571). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Jul 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R218W pathogenic mutation (also known as c.652C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 652. The arginine at codon 218 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with features consistent with Andersen-Tawil syndrome (ATS), including de novo occurrences, has been reported to segregate with disease features in families, and has shown intrafamilial phenotypic variability (Plaster NM et al. Cell. 2001 May;105(4):511-9; Donaldson MR et al. Neurology. 2003 Jun;60(11):1811-6; Tengan CH et al. Arq Neuropsiquiatr. 2006 Sep;64(3A):582-4; Haruna Y et al. Hum Mutat. 2007 Feb;28(2):208; Kimura H et al. Circ Cardiovasc Genet. 2012 Jun;5(3):344-53; Lefter S et al. J Clin Neuromuscul Dis. 2014 Dec;16(2):79-82; Ardissone A et al. Neuromuscul Disord. 2017 Mar;27(3):294-297; Villar-Quiles RN et al. Eur J Neurol. 2022 Aug;29(8):2398-2411). Another variant at the same codon, p.R218Q (c.653G>A), has also been reported in association with ATS (Plaster NM et al. Cell, 2001 May;105:511-9). In assays testing KCNJ2 function, this variant showed functionally abnormal results (Plaster NM. Cell. 2001 May;105(4):511-9; Lange PS. Cardiovasc Res. 2003 Aug;59(2):321-7). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Congenital long QT syndrome

Other:1

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

This variant has been reported in the following publications (PMID:11371347;PMID:12163457;PMID:12796536;PMID:15852530;PMID:16217063;PMID:17074642;PMID:17119796;PMID:17221872;PMID:17399642;PMID:18554214;PMID:20647529). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.90

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Uncertain

0.17

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.5

H;H

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.98

Loss of methylation at R218 (P = 0.0488);Loss of methylation at R218 (P = 0.0488);

MVP

1.0

MPC

2.0

ClinPred

1.0

GERP RS

4.7

Varity_R

0.93

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over