17-70175238-C-T

Position:

chr17-70175238-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000891.3(KCNJ2):c.199C>T(p.Arg67Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R67Q) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KCNJ2
NM_000891.3 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10O:2

Conservation

PhyloP100: 4.12

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 19 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 79) in uniprot entity KCNJ2_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chr17-70175239-G-A is described in Lovd as [Likely_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, 0.989

PP5

Variant 17-70175238-C-T is Pathogenic according to our data. Variant chr17-70175238-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 8923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-70175238-C-T 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.199C>T	p.Arg67Trp	missense_variant	2/2	ENST00000243457.4	NP_000882.1	P63252

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KCNJ2	ENST00000243457.4 linkuse as main transcript	c.199C>T	p.Arg67Trp	missense_variant	2/2	1	NM_000891.3	ENSP00000243457.2		P63252
KCNJ2	ENST00000535240.1 linkuse as main transcript	c.199C>T	p.Arg67Trp	missense_variant	2/2	1		ENSP00000441848.1		P63252

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Andersen Tawil syndrome

Pathogenic:3Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2002	- -
Pathogenic, no assertion criteria provided	research	Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences	Apr 12, 2022	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	Dec 17, 2021	We observed the p.R67W variant in a 29-y.o. female proband, who experienced a cardiac arrest and had a cardioverter-defibrillator implanted for secondary prophylaxis of sudden cardiac death. Extra-cardiac phenotype had included short stature, low-set and rotated ears, hypertelorism, epicanthus, small mandibulae and chin, clinodactyly of the IV-V finders, small hands, and feet, and mild scoliosis. Its effect of p.R67W variatn is described in in vitro studies (PS3 criteria); the variant is absent in large databases (PM2 criteria). The variant was not detected in proband's parents (PM6 criteria). Various in silico tools predict the variant to be deleterious (PP3 criteria), and the p.R67W variant was described previously as pathogenic (PP5 criteria). Based on all the criteria, we consider p.R67W variant to be pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2022	Observed in multiple unrelated patients from different ethnic backgrounds with KCNJ2-related disorders referred for genetic testing at GeneDx and in published literature (Andelfinger et al., 2002; Donaldson et al., 2003; Chun et al., 2004; Davies et al., 2005; Haruna et al., 2007; Kimura et al., 2012; Tan et al., 2012; Jabbari et al., 2013; Lieve et al., 2013; Song et al., 2016); 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; Published functional studies demonstrate the variant alters channel function (Donaldson et al., 2003; Andelfinger et al., 2002); This variant is associated with the following publications: (PMID: 11841151, 22589293, 15851159, 24561538, 23631430, 24025405, 17221872, 16217063, 22806368, 12796536, 20301441, 11861044, 27145478, 31068157, 31509255, 31567646, 23867365, 20713726, 15911703, 26582918, 32499698, 12148092) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 13, 2016	- -

not specified

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 05, 2018

The KCNJ2 c.199C>T; p.Arg67Trp variant (rs104894580), is reported in the literature in multiple individuals and families affected with Andersen-Tawil syndrome (ATS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and isolated periodic paralysis (Andelfinger 2002, Chun 2004, Donaldson 2003, Haruna 2007, Jabbari 2013, Kimura 2012, Lieve 2013, Tan 2012). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 8923), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 67 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show loss of channel function, dominant negative effects, and decreased PIP2 binding that inhibits channel function (Andelfinger 2002, Donaldson 2003). Based on available information, the p.Arg67Trp variant is considered to be pathogenic. References: Andelfinger G et al. KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet. 2002 Sep;71(3):663-8. Chun TU et al. Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm. 2004 Jul;1(2):235-41. Donaldson MR et al. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology. 2003 Jun 10;60(11):1811-6. Haruna Y et al. Genotype-phenotype correlations of KCNJ2 mutations in Japanese patients with Andersen-Tawil syndrome. Hum Mutat. 2007 Feb;28(2):208. Jabbari J et al. New exome data question the pathogenicity of genetic variants previously associated with catecholaminergic polymorphic ventricular tachycardia. Circ Cardiovasc Genet. 2013 Oct;6(5):481-9. Kimura H et al. Phenotype variability in patients carrying KCNJ2 mutations. Circ Cardiovasc Genet. 2012 Jun;5(3):344-53. Lieve KV et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013 Jul;17(7):553-61. Tan SV et al. Membrane dysfunction in Andersen-Tawil syndrome assessed by velocity recovery cycles. Muscle Nerve. 2012 Aug;46(2):193-203. -

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

Oct 31, 2018

- -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 67 of the KCNJ2 protein (p.Arg67Trp). 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: 12148092, 12796536, 17221872, 22589293, 22806368, 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: 8923). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 12148092, 20713726). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 26, 2020

The p.R67W pathogenic mutation (also known as c.199C>T), located in coding exon 1 of the KCNJ2 gene, results from a C to T substitution at nucleotide position 199. The arginine at codon 67 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in multiple individuals with Andersen-Tawil syndrome, including de novo occurrence as well as strong segregation with disease in affected families (Andelfinger G et al. Am. J. Hum. Genet., 2002 Sep;71:663-8; Davies NP et al. Neurology, 2005 Oct;65:1083-9; Haruna Y et al. Hum. Mutat., 2007 Feb;28:208; Delannoy E et al. Europace, 2013 Dec;15:1805-11). This mutation has also been reported in long QT syndrome and primary periodic paralysis cohorts (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61; Luo S et al. BMC Neurol, 2019 May;19:92). Limited functional studies demonstrated significant impact on potassium channel function (Andelfinger G et al. Am. J. Hum. Genet., 2002 Sep;71:663-8). 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:12148092;PMID:12796536;PMID:15851159;PMID:16217063;PMID:17221872). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

D;D

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Pathogenic

0.55

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.7

H;H

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-6.9

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.94

MutPred

0.95

Loss of methylation at R67 (P = 0.02);Loss of methylation at R67 (P = 0.02);

MVP

0.98

MPC

2.0

ClinPred

0.99

GERP RS

2.0

Varity_R

0.86

gMVP

0.98

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