Submissions for variant NM_000891.3(KCNJ2):c.200G>A (p.Arg67Gln)

dbSNP: rs199473368

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170972	SCV000223535	pathogenic	not provided	2015-05-28	criteria provided, single submitter	clinical testing	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).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001218636	SCV001390527	likely pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2019-05-22	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017374	SCV004847643	likely pathogenic	Andersen Tawil syndrome	2019-03-21	criteria provided, single submitter	clinical testing	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.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058295	SCV000089815	not provided	Congenital long QT syndrome		no assertion provided	literature only	This variant has been reported in the following publications (PMID:17221872;PMID:17341397).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000678807	SCV000804991	pathogenic	not specified	2016-02-29	no assertion criteria provided	clinical testing