Submissions for variant NM_000162.5(GCK):c.1087G>A (p.Asp363Asn)

dbSNP: rs1064793134

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003493592	SCV004242346	likely pathogenic	Monogenic diabetes	2024-01-22	reviewed by expert panel	curation	The c.1087G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 363 (p.(Asp363Asn)) of NM_000162.5. This variant was identified in at least 1 individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:19790256, 36257325, internal lab contributor). The individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative antibodies, and three-generation, dominant family history of diabetes (in a family not used for PP1)) (PP4_Moderate; internal lab contributor).This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.869, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1088A>G (p.Asp363Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1087G>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM2_Suporting, PP2, PP3, PM5_Supporting.
GeneDx	RCV000479890	SCV000565032	uncertain significance	not provided	2021-05-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); 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, 32041611)
Genetic Services Laboratory, University of Chicago	RCV000479890	SCV002067393	likely pathogenic	not provided	2019-10-31	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GCK gene demonstrated a sequence change, c.1087G>A, in exon 9 that results in an amino acid change, p.Asp363Asn. The p.Asp363Asn change affects a highly conserved amino acid residue located in domain of the GCK protein that is known to be functional. The p.Asp363Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, MutationTaster, REVEL). This is a novel sequence change that is not present in the large population databases (ExAC and gnomAD). This particular amino acid change has been reported in association with maturity onset diabetes of the young (MODY) but no additional information regarding the clinical presentation or functional studies was provided (PMID: 19790256). Additionally, this group also reported a different missense variant, c.1088A>T(p.Asp363Val), affecting the same amino acid residue in a different family with MODY. Furthermore, the p.Asp363Asn amino acid change occurs in a region of the GCK gene where other missense sequence changes have been described in patients with GCK-MODY. These collective evidences indicate that this sequence change is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002431386	SCV002605096	likely pathogenic	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 rs1064793134 in MODY, yet.
Ambry Genetics	RCV002431386	SCV002730876	uncertain significance	Maturity onset diabetes mellitus in young	2021-04-07	criteria provided, single submitter	clinical testing	The p.D363N variant (also known as c.1087G>A), located in coding exon 9 of the GCK gene, results from a G to A substitution at nucleotide position 1087. The aspartic acid at codon 363 is replaced by asparagine, an amino acid with highly similar properties. This variant was reported in one maturity-onset of diabetes family; however, specific clinical information was not provided (Osbak KK et al. Hum Mutat, 2009 Nov;30:1512-26). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Athena Diagnostics Inc	RCV000479890	SCV002771543	uncertain significance	not provided	2023-06-19	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. This variant has been identified in at least one individual with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging.