Submissions for variant NM_000162.5(GCK):c.677T>C (p.Val226Ala)

dbSNP: rs193922319

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003398574	SCV004102849	likely pathogenic	Monogenic diabetes	2023-10-13	reviewed by expert panel	curation	The c.677T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 226 (p.(Val226Ala)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). 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 0.822, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Ala (PM5_Supporting). In summary, c.677T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PP3, PM2_Supporting, PM5_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029907	SCV000052562	likely pathogenic	Maturity-onset diabetes of the young type 2	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463604	SCV002605143	uncertain risk allele	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 rs193922319 in MODY, yet.
Molecular Genetics Department, Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology	RCV000029907	SCV004801838	likely pathogenic	Maturity-onset diabetes of the young type 2		criteria provided, single submitter	clinical testing	A previously undescribed nucleotide variant creates a missense p.Val226Ala in the GCK gene. The variant was observed in heterozygous state in an individual affected with diabetes. Heterozygous missense variants are reported in patients with Diabetes mellitus, noninsulin-dependent, late onset, 125853, Diabetes mellitus, permanent neonatal 1, 606176, Hyperinsulinemic hypoglycemia, familial, 3, 602485, MODY, type II, 125851. Another missense variant at the same position (p.Val226Met) was previusly described in patients with MODY [Xu et al., 2020, PMID: 31957151; Flannick et al., 2016, PMID: 27080136]. The variant is not present in population database (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as likely pathogenic.