ClinVar Miner

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

dbSNP: rs1001873841
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Total submissions: 4
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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.
Invitae 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).

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