Submissions for variant NM_000162.5(GCK):c.622G>A (p.Ala208Thr)

gnomAD frequency: 0.00001  dbSNP: rs1476637197

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003318505	SCV004022331	pathogenic	Monogenic diabetes	2024-05-12	reviewed by expert panel	curation	The c.622G>A variant in the glucokinase gene, GCK causes an amino acid change of Ala to Thr at codon 210 (p.(Ala208Thr)) of 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 is also predicted to be deleterious by computational evidence, with a REVEL score of 0.905, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an uncomputable Popmax filtering allele frequency in the gnomAD v2.1.1 due to only one copy in the European non-Finnish population and no copies in another subpopulation (PM2_Supporting). This variant was identified in the heterozygous state in 4 unrelated individuals with diabetes/hyperglycemia (PS4; PMID: internal lab contributors). This variant has been detected in the homozygous state in an Individual with permanent neonatal diabetes (PM3_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with 3 informative meioses in 2 families (PP1_Strong; PMID 25015100; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Ala208Thr has RAI<0.50 (PS3_Moderate; PMID: 25015100). Another missense variant, c.623C>T p.Ala208Val, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala208Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3, approved 8/11/2023) PP3, PP2, PM2_Supporting, PP4_Moderate, PM5_Supporting, PS4_Moderate, PM3_Supporting, PP1_Moderate, PS3_Moderate.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000991306	SCV001142710	likely pathogenic	Maturity-onset diabetes of the young type 2	2019-07-03	criteria provided, single submitter	clinical testing