Submissions for variant NM_000162.5(GCK):c.567C>G (p.Ile189Met)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003445462	SCV004174238	likely pathogenic	Monogenic diabetes	2023-12-02	reviewed by expert panel	curation	The c.567C>G variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to methionine, at codon 189 (p.(Ile189Met)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, 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). Another missense variant, c.566T>C, p.Ile189Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ile189Met (PM5_Supporting). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.841, which is greater than the MDEP threshold of 0.70 (PP3). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(PP4_Moderate, internal lab contributors). This occurred in this individual as a de novo occurrence with unconfirmed parental relationships (PS2_Moderate; internal lab contributor). While this variant was identified in the individual mentioned above, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. AMCG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_Supporting, PM5_Supporting, PP2, PP3, PS2_Moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479523	SCV004223417	uncertain significance	not specified	2023-11-07	criteria provided, single submitter	clinical testing	Variant summary: GCK c.567C>G (p.Ile189Met) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251150 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.567C>G has been observed as a putatively de-novo finding (maternity and paternity not confirmed) in at-least one individual reportedly fulfilling the criteria for GCK associated Monogenic Diabetes (antibody negative, personel correspondence with MODY Expert Panel). However, to our knowledge, no occurrence of c.567C>G in individuals affected with Monogenic Diabetes and no experimental evidence demonstrating its impact on protein function have been reported. A different variant located at the same codon, namely c.566T>C (p.Ile189Thr) has been classified as pathogenic by the Clingen MODY expert panel (ClinVar ID 431972) supporting a critical relevance of this Isoleucine reside to GCK protein function. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.