17-70175958-A-G

Position:

• chr17-70175958-A-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000891.3(KCNJ2):​c.919A>G​(p.Met307Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KCNJ2 NM_000891.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32

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 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.946
• PP5: Variant 17-70175958-A-G is Pathogenic according to our data. Variant chr17-70175958-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KCNJ2	NM_000891.3	c.919A>G	p.Met307Val	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.919A>G	p.Met307Val	missense_variant	2/2	1	NM_000891.3	ENSP00000243457	P1
KCNJ2	ENST00000535240.1	c.919A>G	p.Met307Val	missense_variant	2/2	1		ENSP00000441848	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727242

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.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

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

Aug 30, 2023

ClinVar contains an entry for this variant (Variation ID: 519476). 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: 32499698). This variant disrupts the p.Met307 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ2-related conditions (PMID: 17211524, 31567646), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individual(s) with clinical features of Andersen-Tawil syndrome (PMID: 25847018, 31068157, 31483760, 31567646, 32499698; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 307 of the KCNJ2 protein (p.Met307Val). -

Cardiovascular phenotype Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2017

The p.M307V variant (also known as c.919A>G), located in coding exon 1 of the KCNJ2 gene, results from an A to G substitution at nucleotide position 919. The methionine at codon 307 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported as de novo in a Chinese patient with Andersen-Tawil syndrome (ATS) (Liu XL et al. J. Neurol. Sci. 2015 May;352(1-2):105-6). Another alteration involving the same amino acid, p.M307I (c.921G>A), has been reported to segregate with disease in a Korean family with ATS (Choi BO et al. J. Hum Genet. 2007 Jan;52(3):280-3). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Cardiac arrhythmia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 26, 2022

Variant summary: KCNJ2 c.919A>G (p.Met307Val) results in a conservative amino acid change located in the Inward rectifier potassium channel, C-terminal domain (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 251354 control chromosomes. c.919A>G has been reported in the literature as a de-novo variant/sporadic finding in affected individuals with a report of co-segregation in at-least one family affected with features of Andersen Tawil syndrome (ATS) (example, Liu_2015, Alrashed_2019, Ullah_2019, Luo_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Handklo-Jamal_2020). The most pronounced variant effect results in high sensitivity to PIP2 depletion supporting a lability of/impaired PIP2-Kir2.1 interaction. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.63	.;T
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.70		Gain of catalytic residue at M307 (P = 0.1154);Gain of catalytic residue at M307 (P = 0.1154);
MVP		0.97
MPC		2.0
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.86
gMVP		0.81

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: rs1555603994; hg19: chr17-68172099;