ClinVar

Description

This sequence change is predicted to replace arginine with cysteine at codon 34 of the KCNJ11 protein, p.(Arg34Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the cytoplasmic N-terminus domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at an allele frequency of 0.0004% (rs954727530, 1/250,946 alleles in gnomAD v2.1). KCNJ11 has a low tolerance for missense variation and missense change is the predominant mutational mechanism (gnomAD v2.1, DECIPHER, ClinVar). Three probands have been described with this variant with transient neonatal diabetes and congenital hyperinsulinism (PMID: 27908292; 23275527; 17446535). Expression studies show a defect in trafficking (PMID: 12524280). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). An alternate change at the same amino acid residue determine to be pathogenic, p.(Arg34His), has been reported in individuals with congenital hyperinsulinism in monoallelic and biallelic forms (PMID: 31218401, 28270372, 24421282, 24686051, 20685672). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM5, PS3_Supporting, PS4_Supporting, PP2, PP3.