ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1166T>C (p.Val389Ala)

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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 RCV004527574 SCV005040686 uncertain significance Monogenic diabetes 2024-04-28 reviewed by expert panel curation The c.1166T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 389 (p.(Val389Ala)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 19790256). Another missense variant, c.1166T>A p.Val389Asp, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1166T>C meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting.

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