rs1131691505
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2_SupportingPM4
This summary comes from the ClinGen Evidence Repository: The c.1130_1138del variant in the glucokinase gene, GCK, is a 9 base pair deletion resulting in the in-frame deletion of 3 amino acids at codon 377 (p.(Arg377_Ala379del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1130_1138del variant is predicted to change the length of the protein due an in-frame deletion of three amino acids in a non-repeat region (PM4). This variant segregated with hyperglycemia with two informative meioses in one family with MODY, which is below the threshold for PP1 (PMID:31063852). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 31063852, internal lab contributors). This variant was identified in an individual with hyperglycemia, however, PP4 is unable to be evaluated due to insufficient clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM4, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA645369436/MONDO:0015967/086
Frequency
Consequence
NM_000162.5 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.1130_1138del | p.Arg377_Ala379del | inframe_deletion | 9/10 | ENST00000403799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.1130_1138del | p.Arg377_Ala379del | inframe_deletion | 9/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not specified Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 19, 2017 | - - |
Maturity onset diabetes mellitus in young Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic | - | Potent mutations in GCK gene is associated with poor secretion of insulin. Its associated with milder forms of diabetes, which can be controlled by diet . However, there is no sufficient evidence to ascertain the significance of rs1131691505 in MODY, yet. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 11, 2017 | The c.1130_1138delGCGCTGCGC variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This deletion results in the in-frame deletion of three amino acids; the deleted residues Arginine 377 and Alanine 378 are conserved across species, and Alanine 379 is conserved in mammals. Missense changes in the deleted residues (R377S/C/L/H, A378T/G/V/D, A379V/E) 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; however, the possibility that it is benign cannot be excluded. - |
Monogenic diabetes Uncertain:1
Uncertain significance, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Feb 02, 2024 | The c.1130_1138del variant in the glucokinase gene, GCK, is a 9 base pair deletion resulting in the in-frame deletion of 3 amino acids at codon 377 (p.(Arg377_Ala379del)) within exon 9 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The c.1130_1138del variant is predicted to change the length of the protein due an in-frame deletion of three amino acids in a non-repeat region (PM4). This variant segregated with hyperglycemia with two informative meioses in one family with MODY, which is below the threshold for PP1 (PMID: 31063852). This variant was identified in two unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMID 31063852, internal lab contributors). This variant was identified in an individual with hyperglycemia, however, PP4 is unable to be evaluated due to insufficient clinical information. In summary, this variant meets the criteria to be classified as uncertain significance for monogenic diabetes, ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PM4, PM2_Supporting. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at