rs1064794268
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS4PP1_StrongPP4_ModeratePP2PP3PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.113A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 38 (p.(Gln38Pro)) 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 0.887, 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 7 unrelated individuals with hyperglycemia (PS4; PMID:1508276, 11079754, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID:11508276, internal lab contributors). In summary, c.113A>C 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): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16618475/MONDO:0015967/086
Frequency
Consequence
ENST00000403799.8 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.113A>C | p.Gln38Pro | missense_variant | 2/10 | ENST00000403799.8 | NP_000153.1 | |
GCK | NM_033507.3 | c.116A>C | p.Gln39Pro | missense_variant | 2/10 | NP_277042.1 | ||
GCK | NM_033508.3 | c.110A>C | p.Gln37Pro | missense_variant | 3/11 | NP_277043.1 | ||
GCK | NM_001354800.1 | c.113A>C | p.Gln38Pro | missense_variant | 2/11 | NP_001341729.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.113A>C | p.Gln38Pro | missense_variant | 2/10 | 1 | NM_000162.5 | ENSP00000384247 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461856Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1AN XY: 727226
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 20, 2021 | Variant summary: GCK c.113A>C (p.Gln38Pro) results in a non-conservative amino acid change located in the Hexokinase, N-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251464 control chromosomes. c.113A>C has been reported in the literature in individuals affected with Monogenic Diabetes including in a pair of siblings as well as a reported de novo occurrence (Prisco_2000, Massa_2001, Velho_2004, Aloi_2017, Bitterman_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different amino acid change affecting the same codon (p.Gln38Leu) has been reported in association with monogenic diabetes (HGMD). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Mar 19, 2024 | The c.113A>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamine to proline at codon 38 (p.(Gln38Pro)) 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 0.887, 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 7 unrelated individuals with hyperglycemia (PS4; PMID: 1508276, 11079754, internal lab contributors). One of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT 2 hour glucose < 3 mmol/L)(PP4_Moderate; internal lab contributor). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 3 families (PP1_Strong; PMID: 11508276, internal lab contributors). In summary, c.113A>C 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): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting. - |
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2017 | The Q38P variant has been published previously in association with MODY, including an apparently de novo occurrence (Prisco et al., 2000; Massa et al., 2001; Osbak et al., 2009). The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Q38P is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (Q38L) and in nearby residues (V33A, R36W/Q, M37R, E40K, M41T, R43S/G/C/P/H) have been reported in the Human Gene Mutation Database in association with MODY (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 01, 2024 | This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 38 of the GCK protein (p.Gln38Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of maturity onset diabetes of the young (MODY) (PMID: 11079754, 11508276, 28726111, 36227502). ClinVar contains an entry for this variant (Variation ID: 420070). 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 with a negative predictive value of 80%. 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. - |
Maturity-onset diabetes of the young type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Translational Genomics Laboratory, University of Maryland School of Medicine | Jun 07, 2017 | The c.113A>C variant in codon 38 (exon 2) of the glucokinase gene, GCK, results in the substitution of Glutamine to Proline. The c.113A>C variant was previously identified in the patient's nephew, who has a clinical picture consistent with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY). It was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, this variant has been reported in two patients with a MODY2 phenotype (11508276;11079754). Another variant at this codon, Gln38Leu, has been found to co-segregate with fasting hyperglycemia in a different family (K. Colclough, personal communication, April 10, 2017). Additionally, multiple lines of computational evidence (SIFT, LRT, MutationTaster, FATHMM, MetaSVM, MetaLR, CADD, GERP, PROVEAN) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. ACMG Criteria = PS4-mod, PM2, PP1, PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at