ClinVar Miner

Submissions for variant NM_000525.4(KCNJ11):c.902G>A (p.Arg301His)

gnomAD frequency: 0.00001  dbSNP: rs74339576
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000671339 SCV000796303 likely pathogenic Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2 2017-12-11 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001103550 SCV001260322 uncertain significance Diabetes mellitus, transient neonatal, 3 2017-05-30 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV000009220 SCV001260323 uncertain significance Hyperinsulinemic hypoglycemia, familial, 2 2017-05-25 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina RCV001103551 SCV001260324 uncertain significance Maturity-onset diabetes of the young type 13 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Invitae RCV001224980 SCV001397212 pathogenic not provided 2024-01-08 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 301 of the KCNJ11 protein (p.Arg301His). This variant is present in population databases (rs74339576, gnomAD 0.006%). This missense change has been observed in individuals with congenital hyperinsulinism (PMID: 14715863, 15562009, 23275527, 23345197). ClinVar contains an entry for this variant (Variation ID: 8683). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 18250167). This variant disrupts the p.Arg301 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18250167, 20685672, 23275527). 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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002227030 SCV002506471 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. It is also associated with Neonatal Diabetes. However, no sufficient evidence is found to ascertain the role of this particular variant (rs74339576) in MODY yet.
Baylor Genetics RCV003460444 SCV004198065 pathogenic Type 2 diabetes mellitus 2023-05-11 criteria provided, single submitter clinical testing
OMIM RCV000009220 SCV000029438 pathogenic Hyperinsulinemic hypoglycemia, familial, 2 2005-02-01 no assertion criteria provided literature only

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