Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003883182 | SCV004697901 | likely benign | Monogenic diabetes | 2024-12-26 | reviewed by expert panel | curation | The c.142G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 48 (p.(Glu48Lys)) 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). The Popmax filtering allele frequency of the c.142G>A variant in gnomAD v2.1.1 is 0.00001685, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting (0.000003) and BS1 (0.00004); thus, neither criterion will be applied. This variant was observed in unknown phase with the variant c.461T>G p.Val154Gly (internal lab contributors), which is classified as likely pathogenic by the ClinGen MDEP, in an individual with a phenotype highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies)(BP2). This variant segregated with hyperglycemia with two informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant was identified in an individual with normal fasting glucose (BS2; PMID: 23799006, internal lab contributor). This variant has a REVEL score of 0.6959, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. In summary, c.142G>A meets the criteria to be classified as likely benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): BS2, BP2, PP2. |
| Laboratory of Medical Genetics, |
RCV001730073 | SCV001976885 | uncertain significance | Hyperinsulinism due to glucokinase deficiency | 2021-10-06 | criteria provided, single submitter | clinical testing | PM2, PP2, PP3 |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003331193 | SCV004038787 | uncertain significance | not specified | 2023-08-22 | criteria provided, single submitter | clinical testing | Variant summary: GCK c.142G>A (p.Glu48Lys) results in a conservative amino acid change located in the Hexokinase, N-terminal domain (IPR022672) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251436 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.142G>A has been reported in the literature in individuals affected with features of Monogenic Diabetes (example, Donath_2019, Campos Franco_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Monogenic Diabetes. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35472491, 31291970). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Fulgent Genetics, |
RCV005038284 | SCV005668361 | uncertain significance | Type 2 diabetes mellitus; Hyperinsulinism due to glucokinase deficiency; Maturity-onset diabetes of the young type 2; Permanent neonatal diabetes mellitus 1 | 2024-06-04 | criteria provided, single submitter | clinical testing |