ClinVar Miner

Submissions for variant NM_000162.5(GCK):c.646G>A (p.Glu216Lys)

gnomAD frequency: 0.00004  dbSNP: rs778550411
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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 RCV003318502 SCV004022337 uncertain significance Monogenic diabetes 2023-07-30 reviewed by expert panel curation The c.646G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 216 (p.Glu216Lys) of NM_000162.5. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.711, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, 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). The Popmax filtering allele frequency of the c.646G>A variant in gnomAD v2.1.1 is 0.00001897 (East Asian), which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. In summary, c.646G>A 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 1.2.0, approved 6/7/2023): PP3, PP2.
Athena Diagnostics RCV000518502 SCV000613446 uncertain significance not provided 2019-03-30 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002506251 SCV002805566 uncertain significance Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1 2021-09-13 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000518502 SCV003280912 uncertain significance not provided 2022-10-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 216 of the GCK protein (p.Glu216Lys). This variant is present in population databases (rs778550411, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GCK-related conditions. ClinVar contains an entry for this variant (Variation ID: 447412). 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. 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.

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