ClinVar Miner

Submissions for variant NM_000525.4(KCNJ11):c.662G>A (p.Arg221His)

dbSNP: rs768909861
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672836 SCV000797982 uncertain significance Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2 2018-02-22 criteria provided, single submitter clinical testing
Invitae RCV001868266 SCV002293773 uncertain significance not provided 2023-07-17 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 221 of the KCNJ11 protein (p.Arg221His). This variant is present in population databases (rs768909861, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperinsulinism and/or type 2 diabetes mellitus (PMID: 27173951, 33046911). ClinVar contains an entry for this variant (Variation ID: 556784). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002227204 SCV002505957 uncertain significance Hyperinsulinemia 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. It is also associated with Neonatal Diabetes. This particular variant rs768909861 has been studied in Hyperinsulinemic Hypoglycemia cases, but significant association with the phenotype is not seen. More studies are required to ascertain the role of this variant in MODY.
Fulgent Genetics, Fulgent Genetics RCV002493114 SCV002779602 uncertain significance Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2; Type 2 diabetes mellitus; Maturity-onset diabetes of the young type 13; Diabetes mellitus, permanent neonatal 2 2022-04-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV002532135 SCV003679177 uncertain significance Inborn genetic diseases 2021-03-02 criteria provided, single submitter clinical testing The c.662G>A (p.R221H) alteration is located in exon 1 (coding exon 1) of the KCNJ11 gene. This alteration results from a G to A substitution at nucleotide position 662, causing the arginine (R) at amino acid position 221 to be replaced by a histidine (H). The in silico prediction for the p.R221H alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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