ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1343del (p.Gly448fs)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003313358 SCV004012131 pathogenic Monogenic diabetes 2023-06-24 reviewed by expert panel curation The c.1343del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 448 (NM_000162.5), adding 166 novel amino acids before encountering a stop codon (p.(Gly448AlafsTer166)). 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 an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative antibodies, and a three generation family history of diabetes) (PP4_Moderate; internal lab contributor). In summary, the c.1343del variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PP4_Moderate, PM2_Supporting).

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