ClinVar

Description

The c.649G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 217 (p.(Asp217Asn)) of [transcript, e.g. NM_000545.8]. NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00005377, which is greater than the MDEP threshold for BS1 (≥0.0.00004) (BS1). This variant was identified in four unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (internal lab contributors). Additionally, this variant was identified in an individual with a normal fasting glucose (BS2) (internal lab contributor). This variant has been observed in cis with the variant GCK c.781G>A (p.Gly261Arg) (PMID:22611063), which is classified as pathogenic by the ClinGen MDEP (BP2). Lastly, functional studies suggest that the p.Asp217Asn protein has increased activity (RAI=2.0); however, the thermostability and protein interactions were not analyzed and therefore neither PS3 or BS3 can be applied (PMID 22611063). In summary, c.649G>A meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS1, BS2, BP2, PP2.