Submissions for variant NM_000162.5(GCK):c.477C>G (p.Ile159Met)

dbSNP: rs1554335567

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000518112	SCV000613434	uncertain significance	not specified	2016-09-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001821451	SCV002069282	likely pathogenic	not provided	2018-11-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.477C>G, in exon 4 that results in an amino acid change, p.Ile159Met. The p.Ile159Met change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile159Met substitution. Although this particular sequence change has not been previously described, different amino acid substitutions at this same position (p.Ile159Asn, p.Ile159Phe, and p.Ile159Val) have been reported in patients with GCK-related mild hyperglycemia (PMIDs: 28323911, 29056535, 21978167). Furthermore, the p.Ile159Met amino acid change occurs in a region of the GCK gene where other missense sequence changes have been described in patients with GCK-MODY. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464022	SCV002605244	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 rs1554335567 in MODY, yet.