Submissions for variant NM_000162.5(GCK):c.364C>A (p.Leu122Ile)

dbSNP: rs1554335616

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003993664	SCV004812211	likely pathogenic	Monogenic diabetes	2024-03-07	reviewed by expert panel	curation	The c.364C>A variant in the glucokinase gene, GCK, causes an amino acid change of leucine to isoleucine at codon 122 (p.(Leu122Ile)) 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 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). 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 antibody negative) (PP4_Moderate; internal lab contributors). Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.364C>A as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_Supporting, PM5_Supporting, PP2, PP3.
Genetic Services Laboratory, University of Chicago	RCV000504203	SCV000594960	likely pathogenic	Maturity-onset diabetes of the young type 2	2016-10-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV002473026	SCV000613425	likely pathogenic	not provided	2022-03-31	criteria provided, single submitter	clinical testing	This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features of MODY. Multiple individuals have been identified with clinical features associated with this gene who also carry missense variants affecting this codon. At least one of those variants is considered to be likely pathogenic, suggesting this variant may also cause disease.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002464017	SCV002605276	likely 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 rs1554335616 in MODY, yet.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002473026	SCV004509252	uncertain significance	not provided	2023-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 122 of the GCK protein (p.Leu122Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant GCK-related conditions (PMID: 31063852). ClinVar contains an entry for this variant (Variation ID: 435307). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu122 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 32468610). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV002473026	SCV005870320	likely pathogenic	not provided	2024-08-21	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; This variant is associated with the following publications: (PMID: 36257325, 31063852)