Submissions for variant NM_000525.4(KCNJ11):c.617G>A (p.Arg206His)

dbSNP: rs1554901747

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NxGen MDx	RCV001506970	SCV001653803	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 2	2019-12-06	criteria provided, single submitter	clinical testing	The missense variant c.617G>A (p.Arg206His) on exon 1 of KCNJ11 is not found in gnomAD databases (PM2). This variant has several pathogenic computational verdicts (PP3) and is reported in Boodhansingh et al. (PMID 31464105) in 2 unrelated infants affected with congenital hyperinsulinism. Functional data of this variant from the same study shows total loss of efflux (PS3). We interpret c.617G>A to be likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002564187	SCV002951259	pathogenic	not provided	2023-08-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 206 of the KCNJ11 protein (p.Arg206His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant familial hyperinsulinism and/or later‚Äêonset diabetes (PMID: 31291970, 31464105, 32027066). ClinVar contains an entry for this variant (Variation ID: 1162197). 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 KCNJ11 protein function. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 31464105). This variant disrupts the p.Arg206 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25555642, 27908292, 30026763). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Shanghai Diabetes Institute, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine	RCV004719070	SCV005324791	pathogenic	Maturity-onset diabetes of the young type 13	2024-08-31	no assertion criteria provided	case-control