ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.1142T>A (p.Met381Lys)

dbSNP: rs193922266
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Monogenic Diabetes Variant Curation Expert Panel RCV003330318 SCV004037468 likely pathogenic Monogenic diabetes 2023-09-09 reviewed by expert panel curation The c.1142T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 381 (p.(Met381Lys)) 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 0.9459, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The variant was identified in an individual with neonatal diabetes who was homozygous for this variant (PP4; PM3_Supporting; internal lab contributor). Another missense variant, c.1142T>C (p.Met381Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met381Lys has an equal or greater Grantham distance (PM5). In summary, c.1142T>A 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): PP4, PM5, PP2, PP3, PM2_Supporting, PM3_Supporting.
Athena Diagnostics RCV000516508 SCV000613401 uncertain significance not specified 2017-03-24 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003688859 SCV004423085 uncertain significance not provided 2023-01-12 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt GCK protein function. ClinVar contains an entry for this variant (Variation ID: 447383). This variant has not been reported in the literature in individuals affected with GCK-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 381 of the GCK protein (p.Met381Lys).
Fulgent Genetics, Fulgent Genetics RCV005034062 SCV005668333 likely pathogenic Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1 2024-03-08 criteria provided, single submitter clinical testing

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