ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1332del (p.Ser445fs)

dbSNP: rs193922280
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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 RCV003313033 SCV004012152 likely pathogenic Monogenic diabetes 2023-06-20 reviewed by expert panel curation The c.1332del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 445 (NM_000162.5), adding 169 novel amino acids before encountering a stop codon (p.(Ser445ValfsTer169)). 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). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold, and PP4 could not be evaluated due to lack of clinical information (ClinVar ID 36197, internal lab contributor). In summary, the c.1332del variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029860 SCV000052515 likely pathogenic Maturity-onset diabetes of the young type 2 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic RCV002287345 SCV002577631 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 rs193922280 in MODY, yet. This variant is shown to be potentially damaging by insilico analysis.

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