Submissions for variant NM_000891.3(KCNJ2):c.566G>A (p.Arg189Lys)

dbSNP: rs199473381

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170980	SCV000223543	likely pathogenic	not provided	2013-03-21	criteria provided, single submitter	clinical testing	p.Arg189Lys (AGA>AAA): c.566 G>A in exon 2 of the KCNJ2 gene (NM_000891.2). The Arg189Lys variant in the KCNJ2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although Arg189Lys results in a conservative amino acid substitution of one positively charged amino acid with another, it occurs at a position that is conserved across species. In silico analysis predicts Arg189Lys is probably damaging to the protein structure/function. Mutations at this codon (Arg189Ile) and in nearby residues (Pro186Leu, Thr192Ala, Thr192Ile) have been reported in association with ATS, further supporting the functional importance of this codon and this region of the protein. Furthermore, the Arg189Lys variant 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, while Arg189Lys is a good candidate for a disease-causing mutation, with the information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852049	SCV002283923	likely pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2022-04-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 189 of the KCNJ2 protein (p.Arg189Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Anderson-Tawil sydnrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 190812). 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. This variant disrupts the p.Arg189 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ2-related conditions (PMID: 12796536, 27145478), which suggests that this may be a clinically significant amino acid residue. 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.