rs1085307455
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP4_ModeratePM2_SupportingPP2PP3PS2_ModeratePS4PP1_Strong
This summary comes from the ClinGen Evidence Repository: The c.571C>T variant in the glucokinase gene, GCK causes an amino acid change of Arg to Trp at codon 191 (p.(Arg191Trp)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable Popmax filtering allele frequency in gnomAD v2.1 due to only one copy in European non-Finnish population and one copy in another subpopulation, which is less than the MDEP threshold for PM2_Supporting (Popmax filtering FAF <= 0.000003 and <= 2 copies in ENF and ≤1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 100 unrelated individuals with diabetes/hyperglycemia (PS4; PMIDs: 10753050, 22060211, 23295292, 28170077, internal lab contributors). This variant segregated with diabetes with at least 72 informative meioses from 51 families with MODY (PP1_Strong; 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% and negative antibodies) (PP4_Moderate; PMID:23295292). This variant was found de novo in an individual with a phenotype highly specific for GCK-MODY with unconfirmed parental relationships (PS2_Moderate; internal lab contributor). Functional studies demonstrated the p.Arg191Trp 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 Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): PS4, PP1_Strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367401530/MONDO:0015967/086
Frequency
Consequence
NM_000162.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251110Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135760
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461634Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727090
GnomAD4 genome
ClinVar
Submissions by phenotype
Maturity-onset diabetes of the young type 2 Pathogenic:4
PS4, PS3, PP1_Strong, PM6, PP4_Moderate, PM2, PP2, PP3 -
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000426122). Different missense changes at the same codon (p.Arg191Gln, p.Arg191Leu) have been reported to be associated with GCK-related disorder (ClinVar ID: VCV000283358 / PMID: 11508276, 19790256). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Variant summary: GCK c.571C>T (p.Arg191Trp) results in a non-conservative amino acid change located in the N-terminal domain (IPR022672) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251110 control chromosomes (gnomAD). c.571C>T has been reported in the literature in numerous individuals affected with Maturity Onset Diabetes Of The Young 2/Neonatal Diabetes Mellitus (e.g. Vits_2006, Estalella_2007, Santana_2017, Wang_2019). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.572G>A, p.Arg191Gln), supporting the critical relevance of codon 191 to GCK protein function. In addition, at least one publication reported experimental evidence evaluating an impact on protein function, demonstrating that the variant resulted in reduced enzyme activity compared to the wild type (Wang_2019). The following publications have been ascertained in the context of this evaluation (PMID: 28170077, 30592380, 16965331, 17573900). ClinVar contains an entry for this variant (Variation ID: 426122). Based on the evidence outlined above, the variant was classified as pathogenic. -
The c.571C>T variant in codon 191 (exon 6) of the glucokinase gene, GCK, results in the substitution of Arginine to Tryptophan. Missense mutations in GCK, including ones in exon 6, have been reported in patients with Maturity-Onset Diabetes of the Young, Type 2 (MODY2, also called GCK-MODY) (19790256). The c.571C>T variant was not observed in the NHLBI Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium databases; however, the c.571C>T variant was previously identified in individuals with a MODY2 phenotype of Korean, Norwegian, Belgian, Brazilian, French, Japanese, Italian, and British descent (16632067, 18399931, 16965331, 23295292, 18411240, 22060211, 11508276, 10753050) . Other amino acid substitutions at this residue, p.Arg191Gln and p.Arg191Leu, have been found in individuals with a MODY2 phenotype (19790256, 11508276, 16444761, 19309449). Additionally, multiple lines of computational evidence (LRT, MutationTaster, FATHMM, MetaSVM, MetalR, Provean, GERP, CADD) predict this variant is probably damaging to the protein structure, function, or protein-protein interaction. The c.571C>T variant is located within the small domain of the protein, a region considered to be a mutational hotspot (18382660). ACMG criteria = PS4, PM1, PM2, PP1-mod, PP3 -
not provided Pathogenic:4
This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 191 of the GCK protein (p.Arg191Trp). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with hyperglycemia and/or maturity onset diabetes of the young (PMID: 22060211, 23295292, 27269892, 30656436). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 426122). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GCK protein function with a positive predictive value of 80%. This variant disrupts the p.Arg191 amino acid residue in GCK. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16444761, 27256595, 29510678, 30259503). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
DNA sequence analysis of the GCK gene demonstrated a sequence change, c.571C>T, in exon 5 that results in an amino acid change, p.Arg191Trp. The p.Arg191Trp change affects a highly conserved amino acid residue located in a domain of the GCK protein that is known to be functional. The p.Arg191Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in patients with GCK-related maturity onset diabetes of the young (MODY) (PMIDs: 16965331, 18399931, 23295292). Two other pathogenic sequence changes affecting the same p.Arg191 amino acid position (p.Arg191Gln, p.Arg191Leu) have also been reported in patients with GCK-MODY (PMIDs: 11508276, 19790256). These collective evidences indicate that this sequence change is likely pathogenic. -
Published functional studies demonstrate a damaging effect on protein activity and stability (Wang et al., 2019); Located in a mutational hot spot, the hexokinase small domain (Tinto et al., 2008).; Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28170077, 30656436, 24918535, 24804978, 34393998, 10753050, 22060211, 16632067, 18399931, 16965331, 24735133, 27269892, 24430320, 26706916, 23295292, 28012402, 28726111, 19790256, 30592380, 30663027, 31576961, 33046911, 32531870, 31291970, 34108472) -
The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant segregates with disease in multiple families and has been confirmed to occur de novo in one individual with clinical features associated with this gene. 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). -
Maturity onset diabetes mellitus in young Pathogenic:2
The p.R191W pathogenic mutation (also known as c.571C>T), located in coding exon 5 of the GCK gene, results from a C to T substitution at nucleotide position 571. The arginine at codon 191 is replaced by tryptophan, an amino acid with dissimilar properties. This variant has been observed in multiple individuals with maturity-onset diabetes of the young (Ellard S et al. Diabetologia, 2000 Feb;43:250-3; Yorifuji T et al. Pediatr Diabetes, 2012 Feb;13:26-32; Santana LS et al. Clin. Genet., 2017 Oct;92:388-396) and was shown to segregate with disease in a large family (Caetano LA et al. Arq Bras Endocrinol Metabol, 2012 Nov;56:519-24). A disease-causing variant, p.R191Q, has been described in the same codon (Yorifuji T et al. Pediatr Diabetes, 2012 Feb;13:26-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
The p.Arg190Trp (also known as p.Arg191Trp) variant in GCK has been reported in over 20 individuals with maturity-onset diabetes of the young (MODY), including at least 1 de novo occurrence, and segregated with disease in at least 19 affected relatives from 6 families (Massa 2001 PMID: 11508276; Thomson 2003 PMID: 14517956; Yorifuji 2012 PMID: 22060211; Caetano 2012 PMID: 23295292; Kawakita 2014 PMID: 24804978; Tracz 2014 PMID: 24918535; Costantini 2015 PMID: 24735133; Ping Xiao 2016 PMID: 27269892; Santana 2017 28170077; Giuffrida 2017 28012402; Aloi 2017 PMID: 28726111). This variant has also been reported in ClinVar (Variation ID: 426122) and was identified in 0.001% (1/113506) of European and in 0.005% (1/18392) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant MODY. ACMG/AMP Criteria applied: PS4, PM2, PS2, PP3, PP1_Strong. -
GCK-related disorder Pathogenic:1
The GCK c.571C>T variant is predicted to result in the amino acid substitution p.Arg191Trp. This variant has been reported in the heterozygous state to be pathogenic for maturity onset diabetes of the young (MODY) (Caetano. 2012. PubMed ID: 23295292; Yorifuji. 2012. PubMed ID: 22060211). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -
Monogenic diabetes Pathogenic:1
The c.571C>T variant in the glucokinase gene, GCK causes an amino acid change of Arg to Trp at codon 191 (p.(Arg191Trp)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.936, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable Popmax filtering allele frequency in gnomAD v2.1 due to only one copy in European non-Finnish population and one copy in another subpopulation, which is less than the MDEP threshold for PM2_Supporting (Popmax filtering FAF <= 0.000003 and <= 2 copies in ENF and <= 1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in more than 100 unrelated individuals with diabetes/hyperglycemia (PS4; PMIDs: 10753050, 22060211, 23295292, 28170077, internal lab contributors). This variant segregated with diabetes with at least 72 informative meioses from 51 families with MODY (PP1_Strong; 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% and negative antibodies) (PP4_Moderate; PMID: 23295292). This variant was found de novo in an individual with a phenotype highly specific for GCK-MODY with unconfirmed parental relationships (PS2_Moderate; internal lab contributor). Functional studies demonstrated the p.Arg191Trp 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 Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2, approved 6/7/2023): PS4, PP1_Strong, PS2_Moderate, PP4_Moderate, PM2_Supporting, PP2, PP3. -
Type 2 diabetes mellitus;C0342277:Maturity-onset diabetes of the young type 2;C1865290:Hyperinsulinism due to glucokinase deficiency;C5393570:Permanent neonatal diabetes mellitus 1 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at