Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003318495 | SCV004022328 | likely pathogenic | Monogenic diabetes | 2023-07-17 | reviewed by expert panel | curation | The c.1136C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 379 (p.(Ala379Glu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.985, 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 five unrelated individuals with non-autoimmune/insulin-deficient diabetes (PS4_Moderate; PMID 30592380, internal lab contributors). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 30592389) (PP4; internal lab contributors). This variant has been detected in one individual with neonatal diabetes. This individual was compound heterozygous for the variant and a pathogenic variant and was confirmed in trans by parental/family testing (PM3; PMID 30592380). Functional studies demonstrated the p.Ala379Glu protein has RAI<0.5; however, the wild-type kinetic parameters didn’t pass the quality control, and the PS3 cannot be applied (PMID: 30592380). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4, PM3, PS4_Moderate. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000029840 | SCV000052495 | likely pathogenic | Maturity-onset diabetes of the young type 2 | 2019-01-30 | criteria provided, single submitter | clinical testing | Variant summary: GCK c.1136C>A (p.Ala379Glu) results in a non-conservative amino acid change located in the Hexokinase, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with an ExAC z score of 4.39 indicative of a gene relatively intolerant to benign missense variation (ACMG PP3, PP2). The variant was absent in 231278 control chromosomes (gnomAD)(ACMG PM2). c.1136C>A has been reported in the literature in individuals affected with Maturity Onset Diabetes of the Young 2/Neonatal Diabetes Mellitus (Wang_2018, Wildhardt_2010, Osbak_2009). These data indicate that the variant is likely to be associated with disease (ACMG PS4 and PP1-supporting). Experimental evidence evaluating an impact on protein function demonstrated the variant to be kinetically inactivating, with decreased rate of catalysis and decreased affinity for glucose and ATP and thermal instability as demonstrated by decreased enzyme activity at increased incubation temperature; the authors of the study concluded that the changes in enzyme kinetics and thermostability may be the pathogenic mechanisms by which the variant causes hyperglycemia (ACMG PS3). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as uncertain significance. This variant was previously classified as a VUS-possibly pathogenic variant that was converted during ClinVar submission to likely pathogenic in 2011. As summarized above, at-least two new reports indicating its presence in individuals diagnosed with MODY or a related diabetic phenotype supported by functional evidence have emerged since its original classification. Based on the evidence outlined above, until unequivocal co-segregation with disease in additional families/individuals with MODY2/NDM and additional functional studies corroborating the evidence described above is obtained, the variant was conservatively classified as likely pathogenic. |
| Athena Diagnostics Inc | RCV001642240 | SCV000613399 | pathogenic | not provided | 2021-03-16 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one heterozygous individual with clinical features of maturity-onset diabetes of the young, type 2 (MODY2) and in one compound heterozygous individual with neonatal diabetes mellitus, within the same family (PMID: 30592380). This variant appears to occur de novo in one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant results in reduced enzyme activity compared to the wild type (PMID: 30592380). Computational tools predict that this variant is damaging. |
| Ambry Genetics | RCV002444444 | SCV002611504 | likely pathogenic | Maturity onset diabetes mellitus in young | 2020-07-23 | criteria provided, single submitter | clinical testing | The p.A379E variant (also known as c.1136C>A), located in coding exon 9 of the GCK gene, results from a C to A substitution at nucleotide position 1136. The alanine at codon 379 is replaced by glutamic acid, an amino acid with dissimilar properties. This alteration was confirmed in trans with a second disease-causing allele in a patient with neonatal diabetes mellitus (Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Functional analysis revealed that A379E results in decreased enzyme activity as compared to wild-type (Wang Z et al. J Diabetes Investig, 2019 Jul;10:963-971). Based on internal structural analysis, A379E is more destabilizing to the structure of the hexokinase domain of GCK than several pathogenic variants within 20 Å and in the same domain (Petit P et al. Acta Crystallogr. D Biol. Crystallogr., 2011 Nov;67:929-35; Estalella I et al. J. Hum. Genet., 2008 Mar;53:460-466; Miller SP et al. Diabetes, 1999 Aug;48:1645-51; Osbak KK et al. Hum. Mutat., 2009 Nov;30:1512-26). Another alteration at the same codon, p.A379V (c.1136C>T), has been described (Estalella I et al. J. Hum. Genet., 2008 Mar;53:460-466; Weinert LS et al. Diabetes Res. Clin. Pract., 2014 Nov;106:e44-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |