ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1339del (p.Arg447fs)

dbSNP: rs1064795242
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003325957 SCV004032111 pathogenic Monogenic diabetes 2023-09-01 reviewed by expert panel curation The c.1339del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 167 novel amino acids before encountering a stop codon (p.(Arg447GlyfsTer167)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function 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 6 unrelated individuals with non-autoimmune/insulin-deficient diabetes (PMID 22761713; ClinVar ID 421604.2; internal lab contributors) (PS4_Moderate). This variant was identified in individuals with diabetes consistent with a GCK-MODY phenotype; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 22761713, internal lab contributors). This variant segregated with disease with 2 informative meioses in a family with MODY, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributors). In summary, c.1339del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PS4_Moderate.
GeneDx RCV000481054 SCV000570866 likely pathogenic not provided 2016-07-21 criteria provided, single submitter clinical testing The c.1339delC variant in the GCK gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It causes a frameshift starting with codon Arginine 447, changes this amino acid to a Glycine residue and creates a Stop codon at position 167 of the new reading frame, denoted p.Arg447GlyfsX167. c.1339delC was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, this variant is not predicted to cause loss of normal protein function through protein truncation or nonsense-mediated mRNA decay, as it results in protein extension. The variant leads to the final 19 amino acids being replaced by 166 incorrect amino acids. The final 19 amino acids replaced by this variant are important in stabilizing the active and inactive forms of the protein (Molnes et al., 2008). Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.