ClinVar Genomic variation as it relates to human health

The c.1317C>T variant in the glucokinase gene, GCK, is a synonymous (silent) variant at codon 439 (p.(Ile439=)) of NM_000162.5. This synonymous variant is not predicted to impact splicing (SpliceAI score of 0.00 for donor gain, which is less than the MDEP cutoff of 0.2) and is not highly conserved (phyloP100way score of 0.274, which is below the MDEP cutoff of 2.0) (BP4, BP7). This variant is absent in gnomAD v2.1.1 (PM2_Supporting) and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar ID 515200). The MODY probability is unable to be calculated for this individual due to lack of clinical information (ClinVar ID 515200). This variant has been observed in in unknown phase with the variant c.128G>A p.Arg43His (internal lab contributors), which is classified as pathogenic by the ClinGen MDEP (BP2). In summary, c.1317C>T meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3,0, approved 8/11/2023): PM2_Supporting, BP2, BP4, BP7.

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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 rs1554334455 in MODY, yet.