rs199473368

chr17-70175239-G-A

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.200G>A(p.Arg67Gln) 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. 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. R67W) has been classified as 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:4 O:1
• Conservation: PhyloP100: 10.0

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 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 chr17-70175238-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.
• PP2: Missense variant where missense usually causes diseases, KCNJ2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• PP5: Variant 17-70175239-G-A is Pathogenic according to our data. Variant chr17-70175239-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 67560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-70175239-G-A is described in Lovd as [Likely_pathogenic]. Variant chr17-70175239-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNJ2	NM_000891.3	c.200G>A	p.Arg67Gln	missense_variant	2/2	ENST00000243457.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNJ2	ENST00000243457.4	c.200G>A	p.Arg67Gln	missense_variant	2/2	1	NM_000891.3	P1
KCNJ2	ENST00000535240.1	c.200G>A	p.Arg67Gln	missense_variant	2/2	1		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Feb 29, 2016

- -

Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 22, 2019

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg67 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12148092, 12796536, 17221872, 22589293, 22806368, 23867365). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported to affect KCNJ2 protein function (PMID: 12086641, 17221872, 17341397, 24561538). This variant has been observed in individuals affected with Andersen-Tawil syndrome, catecholaminergic polymorphic ventricular tachycardia, and clinical features of long QT syndrome (PMID: 17221872, 17341397, 22589293, 24561538). ClinVar contains an entry for this variant (Variation ID: 67560). This variant is present in population databases (rs199473368, ExAC 0.01%). This sequence change replaces arginine with glutamine at codon 67 of the KCNJ2 protein (p.Arg67Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 28, 2015

p.Arg67Gln (CGG>CAG): c.200 G>A in exon 2 of the KCNJ2 gene (NM_000891.2). The R67Q mutation in the KCNJ2 gene has been reported in association with arrhythmia and ATS (Eckhardt L et al., 2007; Haruna Y et al., 2007; Kimura H et al., 2012; Kalscheur M et al., 2014). Eckhardt et al. (2007) identified R67Q in a 15-year-old male with premature ventricular contractions and non-specific inferior and lateral T-wave changes. This patient did not have facial/skeletal features or periodic paralysis seen in ATS patients. Haruna et al. (2007) reported R67Q in one Japanese patient with ATS. Kimura et al. (2012) reported one patient with an atypical ATS phenotype. Kalscheur et al. (2014) identified R67Q in a 33-year-old women with a CPVT-like phenotype. In vitro studies demonstrated that the presence of this mutation renders KCNJ2 channels non-functional (Eckhardt L et al., 2007; Haruna Y et al., 2007; Kalscheur M et al., 2014). Other missense mutations affecting the same residue (R67W) or a nearby residues (Y68D, D71N, D71Y, D71V) also have been reported in association with KCNJ2-related arrhythmia, further supporting the functional importance of this residue and region of the protein. Furthermore, R67Q was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, R67Q in the KCNJ2 gene is interpreted as a disease-causing mutation. The variant is found in CPVT,LQT panel(s). -

Andersen Tawil syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2019

The p.Arg67Gln variant in KCNJ2 has been reported in 1 individual with Andersen-Tawil syndrome (ATS), 1 individual with a CPVT-like presentation, and 1 individual who was clinically unaffected but had polymorphic PVCs non-specific inferior lateral T-Wave changes (Eckhardt 2007, Haruna 2007, Kimura 2012, Kalscheur 2014). It was absent from large population studies. In vitro functional studies predict a possible loss of function impact (Eckhardt 2007, Kalscheur 2014) and computational prediction tools are consistent with pathogenicity. Heterozygous knock-in mice exhibit ventricular tachycardia after epinephrine and caffeine exposure (Reilly 2018). In addition, another pathogenic variant at this position, p.R67W, has been identified in several individuals with features of ATS. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant ATS. ACMG/AMP criteria applied: PM2, PM5, PS3_Moderate, PP3, PS4_Supporting. -

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:17221872;PMID:17341397). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		1.0	D;D
Vest4		0.90
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.81
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

Other links and lift over

dbSNP: rs199473368; hg19: chr17-68171380; COSMIC: COSV54662288;