ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1151C>T (p.Ala384Val)

dbSNP: rs1583591747
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000992038 SCV001144002 uncertain significance not provided 2018-10-31 criteria provided, single submitter clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002463760 SCV002605087 likely pathogenic Maturity onset diabetes mellitus in young criteria provided, single submitter research Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1583591747 in MODY, yet.
Labcorp Genetics (formerly Invitae), Labcorp RCV000992038 SCV003439539 uncertain significance not provided 2022-04-22 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 804836). This missense change has been observed in individual(s) with maturity onset diabetes of the young (PMID: 24735133, 28170077). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 384 of the GCK protein (p.Ala384Val).
PreventionGenetics, part of Exact Sciences RCV003396574 SCV004120915 likely pathogenic GCK-related disorder 2022-09-17 criteria provided, single submitter clinical testing The GCK c.1151C>T variant is predicted to result in the amino acid substitution p.Ala384Val. Ala384 (α11-helix of large domain) is projected into an hydrophobic region between two helices (α2 and α11) and its replacment with Val may cause bumps with nearby residues (Costantini et al 2015. PubMed ID: 24735133). This variant has been reported in mutiple individuals with maturity onset diabetes of the young (MODY) (Costantini et al 2015. PubMed ID: 24735133; Santana LS et al 2017. PubMed ID: 28170077; Zubkova N et al 2019. PubMed ID: 30663027). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Different substitutions affecting the same amino acid (p.Ala384Thr and p.Ala384Glu) have also been reported in association with MODY (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). This variant is interpreted as likely pathogenic.

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