Submissions for variant NM_000891.3(KCNJ2):c.653G>C (p.Arg218Pro)

dbSNP: rs199473384

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493695	SCV000583372	likely pathogenic	not provided	2017-05-19	criteria provided, single submitter	clinical testing	The R218P variant that is likely pathogenic was identified in the KCNJ2 gene. This variant has been previously reported in at least one family in association with Andersen-Tawil syndrome (ATS) (Krych et al., 2017). The R218P variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R218P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, pathogenic/likely pathogenic missense variants at the same residue (R218Q, R218W) and nearby residues (G215D, N216Y, N216H), have been reported in HGMD, ClinVar and/or reported at GeneDx in association with ATS (Stenson et al., 2014; ClinVar SCV000541389.1; Landrum et al., 2016), supporting the functional importance of this residue and region of the protein.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856985	SCV002290822	likely pathogenic	Andersen Tawil syndrome; Short QT syndrome type 3	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 218 of the KCNJ2 protein (p.Arg218Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with skeletal muscle channelopathies (PMID: 29606556). ClinVar contains an entry for this variant (Variation ID: 430545). 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.Arg218 amino acid residue in KCNJ2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12796536, 17119796, 17221872, 22589293). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.