ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1019+2T>G

dbSNP: rs193929376
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003883121 SCV004697925 pathogenic Monogenic diabetes 2024-02-23 reviewed by expert panel curation The c.1019+2T>G variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. It is predicted to cause an in-frame deletion of biologically-relevant exon 8 of 10, removing an important region of the protein (PVS1). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant segregated with diabetes with 8 informative meioses in a family with MODY (PP1_Strong; PMID 16026363). This variant was identified individuals with diabetes; however, there was insufficient clinical information to evaluate for PP4. This variant has been detected in at least 2 individuals with neonatal diabetes. Of those individuals, 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant, confirmed in trans by parental/family testing (PMID 16026363). 1 individual was homozygous for the variant (PMID 16026363) (PM3). In summary, the evidence supports the classification of c.1019+2T>G as a pathogenic variant for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM2_Supporting, PVS1, PM3, PP1_Strong.
GeneDx RCV000599197 SCV000709948 pathogenic not provided 2018-10-08 criteria provided, single submitter clinical testing The c.1019+2 T>G splice site variant in the GCK gene has been previously reported to segregate with disease in two related families with MODY and permanent neonatal diabetes (Njølstad et al., 2003; Shehadeh et al., 2005). This variant destroys the canonical splice donor site in intron 8, and is expected to cause abnormal gene splicing. The variant is not observed in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic.
Revvity Omics, Revvity RCV000599197 SCV002024233 pathogenic not provided 2020-11-20 criteria provided, single submitter clinical testing
GeneReviews RCV000020164 SCV000040492 pathologic Permanent neonatal diabetes mellitus 2011-07-05 no assertion criteria provided curation Converted during submission to Pathogenic.

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