Submissions for variant NM_000162.5(GCK):c.1142T>G (p.Met381Arg)

dbSNP: rs193922266

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002281721	SCV004022350	likely pathogenic	Monogenic diabetes	2023-07-17	reviewed by expert panel	curation	The c.1142T>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to arginine at codon 381 (p.(Met381Arg)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.9629, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 22060211 (likely same cases as PMID 29927023, PMID 32375122, PMID 2555642, and PMID 24804978 (Kawakita et al 2014)), PMID 24804978, internal lab contributors). At least one of these individuals has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; internal lab contributors). Another missense variant, c.1142T>C (p.Met381Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Arg has a greater Grantham distance (PM5). In summary, the c.1142T>G variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PM5, PS4_Moderate, PP2, PP3, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281721	SCV000052496	likely pathogenic	Monogenic diabetes	2022-07-15	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1142T>G (p.Met381Arg) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain (IPR022673) of the encoded protein sequence. Other missense variants at the same codon, namely, c.1142T>A (p.Met381Lys) and c.1142T>C (p.Met381Thr) have been observed in association with Maturity Onset Diabetes Of The Young supporting the critical relevance of this residue. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 235544 control chromosomes. c.1142T>G has been reported in the literature in at-least three individuals affected with Maturity Onset Diabetes Of The Young 2 who have been subsequently cited by others (example, Yorifuji_2012/2018, Zhou_2020, Bennett_2015, Kawakita_2014). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, the ClinGen Monogenic Diabetes Expert Panel has classified this variant as Likely Pathogenic, citing overlapping evidence utilized in the context of this evaluation (personal correspondence). Based on the evidence outlined above, the variant was classified as likely pathogenic.