Submissions for variant NM_000162.5(GCK):c.437T>C (p.Leu146Pro)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003326023	SCV004032093	pathogenic	Monogenic diabetes	2023-08-13	reviewed by expert panel	curation	The c.437T>C variant in the glucokinase gene, GCK causes an amino acid change of leucine to proline at codon 146 (p.(Leu146Pro)) 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 0.983, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with diabetes/hyperglycemia (PS4_Moderate; PMID: 25015100, 31441606, internal lab contributors). This variant segregated with diabetes/hyperglycemia with 3 informative meioses in 1 family (PP1; internal lab contributors). This variant has been detected in the homozygous state in at least 3 individuals with permanent neonatal diabetes (PP4 and PM3; PMIDs: 25015100, 31441606, internal lab contributor). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Leu146Pro variant has a relative activity index (RAI) <0.50 (PS3_Moderate; PMID: 25015100). In summary, the c.437T>C variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PS4_Moderate, PM3, PP4, PP1, PM2_Supporting, PP2, PP3, PS3_Moderate.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003120282	SCV003800480	pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	The GCK c.437T>C; p.Leu146Pro variant (rs2096280084) is reported in the literature in two individuals affected with maturity-onset diabetes of the young (Osbak 2009) and two individuals affected with neonatal diabetes (Al-Khawaga 2019, Raimondo 2014) with co-segregation shown in a family. Functional analyses of the variant protein show markedly reduced glucokinase activity (Raimondo 2014). A different missense variant at the same residue (p.Leu146Arg) is also determined to be functionally deleterious (Sagen 2006). This variant is not reported in ClinVar and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 146 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.983). Based on available information, this variant is considered to be pathogenic. References: Al-Khawaga S et al. The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Qatar. Mol Genet Genomic Med. 2019 Oct;7(10):e00753. PMID: 31441606. Osbak KK et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009 Nov;30(11):1512-26. PMID: 19790256. Raimondo A et al. Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. Hum Mol Genet. 2014 Dec 15;23(24):6432-40. PMID: 25015100. Sagen JV et al. From clinicogenetic studies of maturity-onset diabetes of the young to unraveling complex mechanisms of glucokinase regulation. Diabetes. 2006 Jun;55(6):1713-22. PMID: 16731834.
GeneDx	RCV003120282	SCV005396345	likely pathogenic	not provided	2024-05-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; 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: 19790256, 25015100, 32971462, 31441606)