Submissions for variant NM_000162.5(GCK):c.1019+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel	RCV003445458	SCV004174228	pathogenic	Monogenic diabetes	2023-11-24	reviewed by expert panel	curation	The c.1019+1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 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). The nucleotide change c.1019+1G>A was identified in 9 unrelated individuals with hyperglycemia (PS4; PMIDs: 15928245, 28726111, 32533152, 28012402, 36257325, internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, 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 and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). The c.1019+1G>T variant at the same canonical nucleotide and has a similar predicted impact by Splice AI (.96 and .96), but PS1_Supporting cannot be applied because the c.1019+1G>T variant is only likely pathogenic before incorporating information about the G>A variant. In summary, c.1019+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS4, PM2_Supporting, PP4_Moderate.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003445458	SCV004223568	pathogenic	Monogenic diabetes	2023-11-09	criteria provided, single submitter	clinical testing	Variant summary: GCK c.1019+1G>A 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 canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 242076 control chromosomes. c.1019+1G>A has been reported in the literature in individuals affected with features of GCK-associated Monogenic Diabetes (example, Johansen_2005, Giuffrida_2017, Aloi_2017). These data indicate that the variant is 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: 28726111, 32533152, 28012402, 15928245, 36257325). 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 pathogenic.