ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.544G>A (p.Val182Met) (rs587780345)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000117131 SCV000151292 pathogenic Gestational diabetes 2013-11-04 criteria provided, single submitter clinical testing
GeneDx RCV000255191 SCV000321714 pathogenic not provided 2015-06-08 criteria provided, single submitter clinical testing The V182M missense variant in the GCK gene has been reported previously in association with MODY (Froguel et al., 1993). The V182M variant is located within one of two domains in the glucokinase protein predicted to be involved in substrate-induced active site closure (Gidh-Jain et al., 1993). The V182M variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret the V182M missense to be a pathogenic variant.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000255191 SCV000337884 pathogenic not provided 2015-11-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000255191 SCV000613440 pathogenic not provided 2017-07-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763586 SCV000894425 pathogenic Permanent neonatal diabetes mellitus; Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young, type 2 2018-10-31 criteria provided, single submitter clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000255191 SCV001448738 pathogenic not provided 2018-02-20 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV001248908 SCV001422601 pathogenic Maturity-onset diabetes of the young, type 2 2020-01-22 no assertion criteria provided curation The p.Val182Met variant in GCK has been reported in at least 9 individuals with maturity-onset diabetes of the young (MODY) type 2, segregated with disease in 4 affected relatives from 2 families (PMID: 29510678, 20337973, 21395678, 25082184, 23771172, 25306193, 25494859), and was absent from large population studies. Animal models in mice have shown that this variant causes MODY type 2 (15102714, 18056790). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for MODY type 2 in an autosomal dominant manner based on the phenotype of mouse models being consistent with human disease, the increased prevalence of the variant in affected individuals, including relatives, compared to controls, and computational evidence. ACMG/AMP Criteria applied: PS3_PM2, PS4_moderate, PP3, PP1 (Richards 2015).

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