Submissions for variant NM_000162.5(GCK):c.1130_1138del (p.Arg377_Ala379del)

dbSNP: rs1131691505

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003493603	SCV004242355	uncertain significance	Monogenic diabetes	2024-02-02	reviewed by expert panel	curation	The c.1130_1138del variant in the glucokinase gene, GCK, is a 9 base pair deletion resulting in the in-frame deletion of 3 amino acids at codon 377 (p.(Arg377_Ala379del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1130_1138del variant is predicted to change the length of the protein due an in-frame deletion of three amino acids in a non-repeat region (PM4). This variant segregated with hyperglycemia with two informative meioses in one family with MODY, which is below the threshold for PP1 (PMID: 31063852). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 31063852, internal lab contributors). This variant was identified in an individual with hyperglycemia, however, PP4 is unable to be evaluated due to insufficient clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM4, PM2_Supporting.
GeneDx	RCV000493930	SCV000582258	likely pathogenic	not provided	2017-05-11	criteria provided, single submitter	clinical testing	The c.1130_1138delGCGCTGCGC variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This deletion results in the in-frame deletion of three amino acids; the deleted residues Arginine 377 and Alanine 378 are conserved across species, and Alanine 379 is conserved in mammals. Missense changes in the deleted residues (R377S/C/L/H, A378T/G/V/D, A379V/E) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Genetic Services Laboratory, University of Chicago	RCV000503344	SCV000594951	likely pathogenic	not specified	2017-09-19	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002463683	SCV002605093	likely pathogenic	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 rs1131691505 in MODY, yet.