Submissions for variant NM_000525.4(KCNJ11):c.119G>A (p.Gly40Asp)

dbSNP: rs1001873841

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000666416	SCV000790704	uncertain significance	Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2	2017-04-06	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002227198	SCV002505959	uncertain significance	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. This particular variant (rs1001873841) association with MODY remains uncertain. More studies are required to ascertain its role in MODY yet.
PreventionGenetics, part of Exact Sciences	RCV004527725	SCV004103864	likely pathogenic	KCNJ11-related disorder	2023-10-11	criteria provided, single submitter	clinical testing	The KCNJ11 c.119G>A variant is predicted to result in the amino acid substitution p.Gly40Asp. This variant has been reported in multiple individuals with congenital hyperinsulinism (Table 1, Suchi et al. 2006. PubMed ID: 16357843; Table 2, Salomon-Estebanez et al. 2016. PubMed ID: 27908292; Table S12, Bonnefond et al. 2020. PubMed ID: 33046911), and in one non-diabetic control (Table S12, Billings et al. 2022. PubMed ID: 36208030). In vitro experimental studies suggest this variant severely affects protein function (Tucker and Ashcroft. 1999. PubMed ID: 10559219). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003558487	SCV004295368	likely pathogenic	not provided	2022-11-29	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Gly40 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ11-related conditions (PMID: 16357843, 24401662, 28123437), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 10559219). 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: 551373). This missense change has been observed in individual(s) with paternally inherited focal hyperinsulinism (PMID: 16357843). This variant has been reported in individual(s) with autosomal dominant diffuse hyperinsulinism (PMID: 27908292); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 40 of the KCNJ11 protein (p.Gly40Asp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586857	SCV005076283	likely pathogenic	Familial hyperinsulinism	2024-04-12	criteria provided, single submitter	clinical testing	Variant summary: KCNJ11 c.119G>A (p.Gly40Asp) results in a non-conservative amino acid change located in the Potassium channel, inwardly rectifying, transmembrane domain (IPR040445) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251188 control chromosomes. c.119G>A has been reported in the literature at a heterozygous state in at-least three individuals affected with Congenital Hyperinsulinism (example, Suchi_2006, Salomon-Estebanez_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disrupted the binding ability of the N-terminal and C-terminal domains of KCNJ11 in vitro and demolished KCNJ11 channel currents on Xenopus oocytes (Tucker_1999). The following publications have been ascertained in the context of this evaluation (PMID: 27908292, 16357843, 10559219). ClinVar contains an entry for this variant (Variation ID: 551373). Based on the evidence outlined above, the variant was classified as likely pathogenic.