ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.629T>A (p.Met210Lys)

dbSNP: rs80356654
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003318493 SCV004022339 pathogenic Monogenic diabetes 2023-07-30 reviewed by expert panel curation The c.629T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 210 (p.(Met210Lys)) 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 0.979, which is greater than the MDEP threshold of 0.70 (PP3), and functional studies suggest that this variant alters glucokinase kinetic parameters, with an RAI less than 0.5 (wild-type QC parameters met including ATP Km between 0.4 and 0.65) (PS3_Moderate; PMIDs: 16731834,14517946). This variant was identified in two unrelated families with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:18399931, 11372010, 27913849, internal lab contributor). At least one individual individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% persisting over time) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes, with at least 10 informative meioses in a family with MODY (PP1_Strong; PMIDs: 18399931, 11372010). This variant has also been detected in at least one family with neonatal diabetes. One individual in this family was homozygous and experienced permanent neonatal diabetes mellitus, and variants were were confirmed in trans (PM3_Supporting; PMIDs:18399931, 11372010). Additionally, another missense variant, c.629T>C (p.Met210Thr) has been interpreted as pathogenic by the ClinGen MDEP, and p.Met210Lyshas a greater Grantham distance (PM5). In summary, c.629T>A 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): PP1_Strong, PM5, PP4_Moderate, PS3_Moderate, PP2, PP3, PM2_Supporting, PM3_Supporting.
Institute of Human Genetics, University of Leipzig Medical Center RCV000190348 SCV004100742 pathogenic Maturity-onset diabetes of the young type 2 2023-10-23 criteria provided, single submitter clinical testing Criteria applied: PM5_STR,PP1_STR,PS4_MOD,PS3_SUP,PM2_SUP,PP3
OMIM RCV001281107 SCV000037793 pathogenic Permanent neonatal diabetes mellitus 1 2001-05-24 no assertion criteria provided literature only
GeneReviews RCV000017521 SCV000040491 not provided Permanent neonatal diabetes mellitus no assertion provided literature only
OMIM RCV000190348 SCV000243895 pathogenic Maturity-onset diabetes of the young type 2 2001-05-24 no assertion criteria provided literature only

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