chr17-70175938-G-T

Position:

• chr17-70175938-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000891.3(KCNJ2):​c.899G>T​(p.Gly300Val) 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. G300D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: 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 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 chr17-70175938-G-A 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, 0.995
• PP5: Variant 17-70175938-G-T is Pathogenic according to our data. Variant chr17-70175938-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 8920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-70175938-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ2	NM_000891.3	c.899G>T	p.Gly300Val	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	c.899G>T	p.Gly300Val	missense_variant	2/2	1	NM_000891.3	ENSP00000243457.2
KCNJ2	ENST00000535240.1	c.899G>T	p.Gly300Val	missense_variant	2/2	1		ENSP00000441848.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNJ2 function (PMID: 12163457, 16834334). 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. ClinVar contains an entry for this variant (Variation ID: 8920). This missense change has been observed in individuals with Andersen-Tawil syndrome (PMID: 12163457, 16419128, 17221872, 31737537). 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 glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 300 of the KCNJ2 protein (p.Gly300Val). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 26, 2018

The G300V variant in the KCNJ2 gene has been reported in multiple individuals with a diagnosis of Andersen-Tawil syndrome (ATS) (Plaster et al., 2001; Haruna et al., 2007; Kamiya et al., 2012; Miyamoto et al., 2015) and was observed to segregate with disease in a least one affected family member (Haruna et al., 2007). The G300V variant has additionally been reported in two siblings diagnosed with LQTS before 1 year of age (Miyazaki et al., 2016). Additionally, this variant is not observed in large population cohorts (Lek et al., 2016). The G300V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Moreover, functional studies in CHO cells have showed that G300V failed to yield any measurable potassium current, and additional assays of G300V have demonstrated a dominant-negative suppression of Kir2.1 channel function (Lange et al., 2003; Tristani-Firouzi et al., 2002; Bendahhou et al., 2003). Finally, a different variant at the same residue (G300D) and variants in nearby residues (E299V, M301L, M301R, M301K) have been classified as likely pathogenic/pathogenic at GeneDx, further supporting the functional importance of this residue and region of the protein. -

Andersen Tawil syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 18, 2001

- -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2024

The p.G300V pathogenic mutation (also known as c.899G>T), located in coding exon 1 of the KCNJ2 gene, results from a G to T substitution at nucleotide position 899. The glycine at codon 300 is replaced by valine, an amino acid with dissimilar properties. This variant was reported in several individuals with features consistent with Andersen-Tawil syndrome, and has been reported to segregate with disease features in families (Plaster NM et al. Cell, 2001 May;105:511-9; Tristani-Firouzi M et al. J Clin Invest, 2002 Aug;110:381-8; Yoon G et al. Am J Med Genet A, 2006 Feb;140:312-21; Haruna Y et al. Hum Mutat, 2007 Feb;28:208; Miyazaki A et al. JACC Clin Electrophysiol, 2016 Jun;2:266-276). In multiple assays testing KCNJ2 function, this variant showed functionally abnormal results (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; Lange PS et al. Cardiovasc Res, 2003 Aug;59:321-7). 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

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:17221872;PMID:22002906). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Pathogenic	0.77	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.5	H;H
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-8.6	D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;D
Vest4		1.0
MutPred		0.97		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		1.0
MPC		2.2
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.95

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: rs104894579; hg19: chr17-68172079;