rs1057524903
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000162.5(GCK):c.1016A>G(p.Glu339Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E339D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000162.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.1016A>G | p.Glu339Gly | missense_variant | 8/10 | ENST00000403799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.1016A>G | p.Glu339Gly | missense_variant | 8/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:2
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Feb 28, 2024 | The c.1016A>G variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glycine at codon 339 (p.(Glu339Gly)) 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 0.993, 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 8 unrelated individuals with hyperglycemia (PS4; ClinVar: 393450, PMIDs: 18399931, 16731834, internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 1 family (PP1; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.06, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 16731834). Another missense variant, c.1015G>A p.Glu339Lys, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1016A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PS3_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting, PP1. - |
Pathogenic, criteria provided, single submitter | clinical testing | Translational Genomics Laboratory, University of Maryland School of Medicine | Jun 03, 2016 | The c.1016A>G variant in codon 339 (exon 8) of the glucokinase gene, GCK, results in the substitution of Glutamic acid to Glycine. This variant was originally reported to co-segregate with diabetes in a Norwegian family with a phenotype consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (16731834). It was subsequently shown to track with diabetes in six additional Norwegian families (18399931). Functional studies on recombinant p.(Glu339Gly) showed reduced enzyme activity and decreased affinity for glucose (16731834). A different amino acid substitution at this residue, p.(Glu339Lys), was found to track with the MODY2 phenotype across three generations of a Chinese family (21104275). Functional studies on p.(Glu339Lys) demonstrated decreased protein yield, lower glucose and ATP affinity, and decreased thermal stability compared to wildtype (21104275). The c.1016A>G variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases. Multiple lines of computational evidence (SIFT, Polyphen, MutationTaster, MutationAssessor, LRT, FATHMM, SVM, LR, CADD, GERP) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS3, PM2, PM5, PP1, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at