Submissions for variant NM_000162.5(GCK):c.171G>A (p.Met57Ile)

dbSNP: rs1057520109

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479407	SCV000565029	likely pathogenic	not provided	2020-11-18	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24323243)
Ambry Genetics	RCV002402377	SCV002713623	likely pathogenic	Maturity onset diabetes mellitus in young	2019-11-11	criteria provided, single submitter	clinical testing	The p.M57I variant (also known as c.171G>A), located in coding exon 2 of the GCK gene, results from a G to A substitution at nucleotide position 171. The methionine at codon 57 is replaced by isoleucine, an amino acid with highly similar properties. This variant was reported to occur de novo in a an individual with maturity-onset diabetes of the young (MODY) (Stanik J et al. Diabetologia. 2014;57:480-4). Based on internal structural analysis, p.M57I is predicted to be moderately destabilizing to the structure near residues involved in binding to glucokinase regulatory protein, and p.M57I is predicted to be more destabilizing than a nearby pathogenic variant (p.S263P) (Beck T et al. Biochemistry. 2013;52(36):6232-9). Other variants affecting this codon (p.M57R, c.170T>G and p.M57T, c.170T>C) have been detected in MODY cohorts however, clinical details were limited (Osbak KK et al. Hum Mutat. 2009;30(11):1512-26; Borowiec M et al. Clin Genet. 2012;82(6):587-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.