ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1284_1362del (p.Arg429fs)

dbSNP: rs2096270423
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003399058 SCV004102854 likely pathogenic Maturity-onset diabetes of the young type 2 2023-11-03 reviewed by expert panel curation The c.1284_1362del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 429 (NM_000162.5), adding 159 novel amino acids before encountering a stop codon (p.(Arg429fsX159)). 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 in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two individuals with diabetes/hyperglycemia consistent with GCK-MODY; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributors). In summary, c.1284_1362del 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): PVS1, PM2_supporting.
Athena Diagnostics RCV001288978 SCV001476453 pathogenic not provided 2020-03-03 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002287492 SCV002577627 uncertain significance 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 rs2096270423 in MODY, yet. This variant is shown to be potentially damaging by insilico analysis.

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