rs104894578

chr17-70175691-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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. R218L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12 O:2
• Conservation: PhyloP100: 2.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000891.3
• 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-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, KCNJ2
• 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/exons	MANE	UniProt
KCNJ2	NM_000891.3	c.652C>T	p.Arg218Trp	missense_variant	2/2	ENST00000243457.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ2	ENST00000243457.4	c.652C>T	p.Arg218Trp	missense_variant	2/2	1	NM_000891.3	P1
KCNJ2	ENST00000535240.1	c.652C>T	p.Arg218Trp	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2023	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) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 28, 2022	- -

Andersen Tawil syndrome Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Jan 18, 2018	PM2, PM5, PP2, PP3, PP4, PP5 -
Likely pathogenic, criteria provided, single submitter	research	Center of Excellence for Medical Genomics, Chulalongkorn University	Oct 05, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 18, 2001	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	case-control	Genetics Laboratory, Department of Biology, Semnan University	Jan 06, 2020	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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 12, 2023

ClinVar contains an entry for this variant (Variation ID: 8919). 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) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ2 protein function. 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. 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. This variant is not present in population databases (gnomAD no frequency). 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). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 19, 2022

The c.652C>T (p.R218W) alteration is located in exon 2 (coding exon 1) of the KCNJ2 gene. This alteration results from a C to T substitution at nucleotide position 652, causing the arginine (R) at amino acid position 218 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in multiple unrelated patients with Andersen-Tawil syndrome (Plaster, 2001; Donaldson, 2003; Davies, 2005; Tengan, 2006; Haruna, 2007; Kimura, 2012; Lefter, 2014). In addition, an alteration affecting the same amino acid, p.R218Q was reported as disease-causing (Plaster, 2001; Kimura, 2012; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. Experimental studies have shown that this missense change alters KCNJ2 channel assembly and has a dominant negative effect on channel function (Lange, 2003; Decher, 2007). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

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: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	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.94	D
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	D
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

Other links and lift over

dbSNP: rs104894578; hg19: chr17-68171832; COSMIC: COSV54662579;