rs199473368
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_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
Consequence
NM_000891.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KCNJ2 | NM_000891.3 | c.200G>A | p.Arg67Gln | 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.200G>A | p.Arg67Gln | missense_variant | 2/2 | 1 | NM_000891.3 | ENSP00000243457.2 | ||
KCNJ2 | ENST00000535240.1 | c.200G>A | p.Arg67Gln | missense_variant | 2/2 | 1 | ENSP00000441848.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
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 | Labcorp Genetics (formerly Invitae), Labcorp | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at