ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1160C>T (p.Ala387Val) (rs193921338)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029845 SCV000052500 likely pathogenic Maturity-onset diabetes of the young, type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
GeneDx RCV000493278 SCV000582616 likely pathogenic not provided 2015-12-03 criteria provided, single submitter clinical testing The A387V variant has been previously published in association with GCK-MODY (Thomson et al., 2003; Pruhova et al., 2010). The 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. A387V is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species within the hexokinase domain; however, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in the same residue (A387E/T) and in nearby residues (G385R/W/V, L386V, G388D) 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. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded
Broad Institute Rare Disease Group,Broad Institute RCV001248970 SCV001422802 uncertain significance Monogenic diabetes 2020-01-22 no assertion criteria provided curation The p.Ala387Val variant in GCK has been reported in at least 4 individuals (including 1 Czech individual, 1 Asian individual, and 1 Caucasian individual from the UK) with Monogenic Diabetes (PMID: 14517956, 19790256, 20337973), and has been identified in 0.003400% (1/29414) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs193921338). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a dominant frequency for a disease with clinical variability/reduced penetrance. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported likely pathogenic in ClinVar (Variation ID: 36182). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Multiple variants in the same region as p.Ala387Val have been reported in association with disease in ClinVar, suggesting that this variant is in an important functional domain and slightly supports pathogenicity (Variation ID: 435300, 36180, 36179). Two additional variants (p.Ala387Glu and p.Ala387Thr) causing a different amino acid change at the same position have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 19790256; Variation ID: 36181). The number of missense variants reported in GCK in the general population is lower than expected, suggesting there is little benign variation in this gene and slightly increasing the possibility that a missense variant in this gene may not be tolerated. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM2_Supporting, PP2, PP3, PS4_Supporting, PM1_Supporting (Richards 2015).

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