Submissions for variant NM_000525.4(KCNJ11):c.616C>T (p.Arg206Cys)

gnomAD frequency: 0.00001  dbSNP: rs775204908

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV001817986	SCV002069645	likely pathogenic	not provided	2020-11-17	criteria provided, single submitter	clinical testing	The p.Arg206Cys change affects a highly conserved amino acid residue located in a domain of the KCNJ11 protein that is known to be functional. The p.Arg206Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in a patient with neonatal hypoglycemia who was later diagnosed with diazoxide responsive congenital hyperinsulinism (PMID: 30026763). This variant was reported to be maternally inherited from a mother with uncontrolled gestational diabetes. It has also been reported in a family with congenital hyperinsulinism (CHI), other details not known (PMID: 25555642). Additionally, different sequence changes affecting the same amino acid residue (p.Arg206Leu and p.Arg206His) have also been described in patients with diazoxide responsive-CHI (PMIDs:31464105, 27908292). This sequence change has been described in the gnomAD database with a low population frequency of 0.0012% (dbSNP rs775204908).
Invitae	RCV001817986	SCV002296176	pathogenic	not provided	2023-03-08	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 31464105; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 12524280). 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. ClinVar contains an entry for this variant (Variation ID: 1338615). This missense change has been observed in individuals with autosomal dominant familial hyperinsulinism (PMID: 25555642, 27908292, 30026763). This variant is present in population databases (rs775204908, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 206 of the KCNJ11 protein (p.Arg206Cys).
GeneDx	RCV001817986	SCV002588047	likely pathogenic	not provided	2022-10-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12524280, 25555642, 29417725, 27908292, 30026763)
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003336445	SCV004046434	likely pathogenic	KCNJ11-related disorder		criteria provided, single submitter	clinical testing	This variant has been previously reported as a heterozygous change in at least two individuals with congenital hyperinsulinism (PMID: 30026763, 25555642). Different amino acid changes at the same residue (p.Arg206His) and (p.Arg206Leu) have been previously reported in individuals with hyperinsulinism and diabetes (PMID: 31291970, 32027066, 27908292). The c.616C>T (p.Arg206Cys) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.001% (3/248626) and thus is presumed to be rare. The c.616C>T (p.Arg206Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.616C>T (p.Arg206Cys) variant is classified as Likely Pathogenic.