Submissions for variant NM_000162.5(GCK):c.463A>G (p.Arg155Gly)

dbSNP: rs193922301

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV004527306	SCV005040696	uncertain significance	Monogenic diabetes	2024-04-18	reviewed by expert panel	curation	The c.463A>G variant in the glucokinase gene, GCK, causes an amino acid change of arginine to glycine at codon 156 (p.(Arg155Gly)) 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 0.794, 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 two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.463A>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PP3, PP2.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029886	SCV000052541	likely pathogenic	Maturity-onset diabetes of the young type 2	2011-08-18	criteria provided, single submitter	curation	Converted during submission to Likely pathogenic.
GeneDx	RCV001753431	SCV001988106	uncertain significance	not provided	2022-06-10	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); Has not been previously published as pathogenic or benign to our knowledge
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002336094	SCV002605248	uncertain 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 rs193922301 in MODY, yet.
Ambry Genetics	RCV002336094	SCV002639881	uncertain significance	Maturity onset diabetes mellitus in young	2022-01-04	criteria provided, single submitter	clinical testing	The p.R155G variant (also known as c.463A>G), located in coding exon 4 of the GCK gene, results from an A to G substitution at nucleotide position 463. The arginine at codon 155 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001753431	SCV003302880	uncertain significance	not provided	2023-11-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 155 of the GCK protein (p.Arg155Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GCK-related conditions. ClinVar contains an entry for this variant (Variation ID: 36223). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function with a negative predictive value of 80%. 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.