chr17-70175692-G-A

Position:

chr17-70175692-G-A

Variant summary

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

The NM_000891.3(KCNJ2):c.653G>A(p.Arg218Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R218W) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

KCNJ2
NM_000891.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 10.0

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:

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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 chr17-70175691-C-T is described in Lovd as [Pathogenic].

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KCNJ2. . Gene score misZ 2.7459 (greater than the threshold 3.09). Trascript score misZ 3.9347 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.992

PP5

Variant 17-70175692-G-A is Pathogenic according to our data. Variant chr17-70175692-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 67585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-70175692-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ2	NM_000891.3 linkuse as main transcript	c.653G>A	p.Arg218Gln	missense_variant	2/2	ENST00000243457.4	NP_000882.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4 linkuse as main transcript	c.653G>A	p.Arg218Gln	missense_variant	2/2	1	NM_000891.3	ENSP00000243457	P1
KCNJ2	ENST00000535240.1 linkuse as main transcript	c.653G>A	p.Arg218Gln	missense_variant	2/2	1		ENSP00000441848	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Andersen Tawil syndrome

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Blueprint Genetics	Oct 27, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jun 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 13, 2024	Variant summary: KCNJ2 c.653G>A (p.Arg218Gln) results in a conservative amino acid change located in the Inward rectifier potassium channel, C-terminal (IPR041647) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 252048 control chromosomes. c.653G>A has been reported in the literature in multiple individuals affected with Andersen-Tawil Syndrome (e.g. Plaster_2001, Tristani-Firouzi_2002, Haruna_2007, Choi_2007). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.652C>T, p.Arg218Trp), supporting the critical relevance of codon 218 to KCNJ2 protein function. Multiple publications report experimental evidence and indicate an impact on protein function (Tristani-Firouzi_2002, Seebohm_2012, Bendahhou_2003). The following publications have been ascertained in the context of this evaluation (PMID: 12796536, 17221872, 11371347, 12163457, 14522976, 22002906, 17211524). ClinVar contains an entry for this variant (Variation ID: 67585). Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 218 of the KCNJ2 protein (p.Arg218Gln). 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: 11371347, 12163457, 17211524, 17221872, 22589293, 23644778, 23867365). 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: 67585). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCNJ2 protein function. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 11371347, 12086641, 14522976, 16834334, 22002906). This variant disrupts the p.Arg281 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11371347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 28, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate this variant exerts a dominant-negative effect on channel function (Bendahhou et al., 2003; Tristani-Firouzi et al., 2002); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17211524, 32843460, 12909315, 22002906, 12163457, 17221872, 23867365, 11371347, 26109178, 16769944, 16834334, 16419128, 30298493, 23644778, 22581653, 12086641, 31509255, 31737537, 32810216, 32383558, 33094497, 33345742, 35460302, 35456365, 14522976, 22589293, 34919635) -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 23, 2019

The p.R218Q pathogenic mutation (also known as c.653G>A), located in coding exon 1 of the KCNJ2 gene, results from a G to A substitution at nucleotide position 653. The arginine at codon 218 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in multiple individuals with Andersen-Tawil syndrome (ATS), and has been reported to segregate with ATS in families (Plaster NM et al. Cell, 2001 May;105:511-9; Haruna Y et al. Hum. Mutat., 2007 Feb;28:208; Jagodziska M et al. Ann Noninvasive Electrocardiol, 2016 Mar;21:189-95; Choi BO et al. J. Hum. Genet., 2007 Jan;52:280-3; Choi BO et al. J. Hum. Genet., 2007 Jan;52:280-3). In vitro functional assays have indicated this variant to result in reduced channel current, and dominant negative effect (Tristani-Firouzi M et al. J. Clin. Invest., 2002 Aug;110:381-8; Bendahhou S et al. J. Biol. Chem., 2003 Dec;278:51779-85; Bendahhou S et al. J. Biol. Chem., 2003 Dec;278:51779-85). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Congenital long QT syndrome

Other:1

not provided, no classification provided

literature only

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

This variant has been reported in the following publications (PMID:11371347;PMID:12163457;PMID:17211524;PMID:17221872;PMID:22002906). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.95

D;D

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

.;D

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.99

MutPred

0.98

Loss of MoRF binding (P = 0.0382);Loss of MoRF binding (P = 0.0382);

MVP

0.99

MPC

2.1

ClinPred

0.99

GERP RS

5.8

Varity_R

0.81

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