ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.113A>C (p.Gln38Pro) (rs1064794268)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480480 SCV000568576 likely pathogenic not provided 2017-03-09 criteria provided, single submitter clinical testing The Q38P variant has been published previously in association with MODY, including an apparently de novo occurrence (Prisco et al., 2000; Massa et al., 2001; Osbak et al., 2009). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Q38P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (Q38L) and in nearby residues (V33A, R36W/Q, M37R, E40K, M41T, R43S/G/C/P/H) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic.
Translational Genomics Laboratory,University of Maryland School of Medicine RCV000754804 SCV000882453 likely pathogenic Maturity-onset diabetes of the young, type 2 2017-06-07 criteria provided, single submitter clinical testing The c.113A>C variant in codon 38 (exon 2) of the glucokinase gene, GCK, results in the substitution of Glutamine to Proline. The c.113A>C variant was previously identified in the patient's nephew, who has a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY). It was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported in two patients with a MODY2 phenotype (11508276;11079754). Another variant at this codon, Gln38Leu, has been found to co-segregate with fasting hyperglycemia in a different family (K. Colclough, personal communication, April 10, 2017). Additionally, multiple lines of computational evidence (SIFT, LRT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD, GERP, PROVEAN) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS4-mod, PM2, PP1, PP3

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