ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1364T>A (p.Val455Glu) (rs753795627)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000711767 SCV000842161 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000711767 SCV001155071 likely pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV001507007 SCV001656248 pathogenic Maturity onset diabetes mellitus in young 2018-07-20 criteria provided, single submitter clinical testing The c.1364T>A (rs753795627) variant is located in exon 10 of the GCK gene, and results in the replacement of valine with glutamate at amino acid position 455 of the glucokinase protein. This variant has been seen in our laboratory in a pediatric patient with fasting hyperglycemia, and it has been reported in the medical literature in one individual with elevated fasting blood glucose (PMID: 19002431). The p.Val455Glu change has also been experimentally demonstrated to cause a decrease in GCK protein function (PMID: 18481947). The variant is rare in the general population (GnomAD) and the substitution occurs at a position that is highly conserved across species. The Val455 residue is located within the GCK domain that contains the allosteric activator site which is particularly vulnerable to substitutions (PMID: 18450771). In addition, a different alteration at the same amino acid residue (p.Val455Met) that is activating has been associated with hyperinsulinism, further indicating that this amino acid is functionally important (PMIDs: 10455021, 10525657). This phenomenon of opposing clinical phenotypes where activating GCK variants (p.Val455Met) cause hyperinsulinism and inactivating variants (p.Val455Glu) cause hyperglycemia is described in the literature (PMID: 19884385 and others). In summary, this variant is interpreted as pathogenic and is consistent with a genetic diagnosis of GCK-MODY.

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