Submissions for variant NM_000162.5(GCK):c.232G>T (p.Asp78Tyr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004798038	SCV005420249	pathogenic	Monogenic diabetes	2024-12-02	reviewed by expert panel	curation	The c.232G>T variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to tyrosine at codon 78 (p.(Asp78Tyr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.993, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthermore, this variant resides in an amino acid that directly binds ATP, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). One of the individuals harboring this variant had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antiboides) (PP4_Moderate; internal lab contributors). While this variant segregated with diabetes with two informative meioses in a single family; this does not meet the thresholds for PP1 set by the ClinGen MDEP (internal lab contributors). Two other missense variants, c.234C>G (p.Asp78Glu) and c.232G>C (p.Asp78His) have been interpreted as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.232G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP2, PP3, PM1, PP4_Moderate, PM5_Strong).
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224686	SCV003920010	uncertain significance	Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1	2021-03-30	criteria provided, single submitter	clinical testing	GCK NM_000162.3 exon 3 p.Asp78Tyr (c.232G>T): This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Of note, other variants at this same codon (p.Asp78Glu, p.Asp78His, p.Asp78Gly) have been reported in the literature, suggesting that this region has significance. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.