ClinVar

Description

A variant of uncertain significance has been identified in the KCNJ10 gene. The R348H variant has been published as a non-synonymous SNP in a patient with congenital hyperinsulinism of infancy (Proverbio et al., 2013). Additionally, the R348H variant has been reported previously in a patient with epileptic spasms, severe intellectual disability, autism spectrum disorder, and EEG abnormalities as well as in her father who has EEG abnormalities and a severe anxiety disorder (Sicca et al., 2016). Functional studies suggest that the R348H variant may affect channel function (Sicca et al., 2016). A different amino acid substitution at the same position (R348C) was reported in a patient with enlarged vestibular aqueduct syndrome who also had a single pathogenic variant in the SLC26A4 gene (Yang et al., 2009). Of note, the patient's unaffected mother and unaffected sibling also had the R348C variant in the KCNJ10 gene (Yang et al., 2009). The R348H variant is observed in 37/66,576 (0.06%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R348H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.