rs1555603994
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M307I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000891.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
KCNJ2 | NM_000891.3 | c.919A>G | p.Met307Val | missense_variant | 2/2 | ENST00000243457.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
KCNJ2 | ENST00000243457.4 | c.919A>G | p.Met307Val | missense_variant | 2/2 | 1 | NM_000891.3 | P1 | |
KCNJ2 | ENST00000535240.1 | c.919A>G | p.Met307Val | missense_variant | 2/2 | 1 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727242
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Andersen Tawil syndrome;C1865018:Short QT syndrome type 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at