Submissions for variant NM_000162.5(GCK):c.680-2A>G

dbSNP: rs1562715657

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV002298750	SCV004697920	pathogenic	Monogenic diabetes	2024-02-28	reviewed by expert panel	curation	The c.680-2A>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 6 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 7 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4: PMIDs: 19790256, 31704690, 36257325, 34362814, ClinVar ID:585924). At least 2 of these individuals had a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 31704690). In summary, c.680-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3, approved 8/11/2023): PVS1, PS4, PM2_Supporting.
Athena Diagnostics	RCV000711782	SCV000842179	pathogenic	not provided	2017-12-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000711782	SCV001764922	pathogenic	not provided	2023-07-01	criteria provided, single submitter	clinical testing	Observed in families with MODY in published literature; however, specific patient information was not provided (Osbak et al., 2009); Not observed in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 19790256)
Genetic Services Laboratory, University of Chicago	RCV000711782	SCV002069670	pathogenic	not provided	2021-02-23	criteria provided, single submitter	clinical testing	DNA sequence analysis of the GCK gene demonstrated a sequence change in the canonical splice acceptor site of intron 6, c.680-2A>G. This sequence change is absent from the gnomAD population database. This sequence change has been previously described in individuals with maturity-onset diabetes of the young (MODY) (PMID: 19790256). This sequence change is predicted to affects mRNA splicing and is likely to result in an absent or truncated protein. Collectively, these evidences indicate that this sequence change is pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002298750	SCV002598565	pathogenic	Monogenic diabetes	2024-01-23	criteria provided, single submitter	clinical testing	Variant summary: GCK c.680-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the 3' canonical acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249710 control chromosomes. c.680-2A>G has been reported in the literature in multiple individuals affected with Monogenic Diabetes (examples: Osbak_2009, Carlsson_2020, Mirshahi_2022). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31704690, 36257325, 19790256). ClinVar contains an entry for this variant (Variation ID: 585924). Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002360845	SCV002605137	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 rs1562715657 in MODY, yet.
Ambry Genetics	RCV002360845	SCV002665064	likely pathogenic	Maturity onset diabetes mellitus in young	2016-02-12	criteria provided, single submitter	clinical testing	The c.680-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 7 in the GCK gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.680-2A>G variant is classified as likely pathogenic.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV004719971	SCV005326355	pathogenic	Maturity-onset diabetes of the young type 2		criteria provided, single submitter	clinical testing	The c.680-2A>G canonical splice site variant results from A to G substitution two nucleotides upstream from coding exon 7 in the GCK gene. The variant is predicted to affect mRNA splicing, resulting in translational frameshift and loss of protein function. This variant has previously been reported in multiple unrelated individuals with GCK-related maturity-onset diabetes of the young (GCK-MODY, MIM: 125851) (PMID: 19790256, PMID: 31704690, PMID: 36257325). This variant is rare in large population studies (1 of 672,852 alleles, gnomAD v4.0.0). Other variants at this position have also been reported in affected individuals (PMID: 8446612, PMID: 31063852).