7-44145638-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5_SupportingPP1_StrongPP2PP3
This summary comes from the ClinGen Evidence Repository: The c.1112G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 371 (p.(Cys371Tyr)) 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 0.956, 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 segregated with diabetes with 5 informative meioses in a family with diabetes/hyperglycemia (PP1_Strong; internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Tyr)(PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GENE-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA367398935/MONDO:0015967/086
Frequency
Consequence
NM_000162.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 09, 2023 | The c.1112G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 371 (p.(Cys371Tyr)) 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 0.956, 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 segregated with diabetes with 5 informative meioses in a family with diabetes/hyperglycemia (PP1_Strong; internal lab contributors). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.(Cys371Tyr)(PM5_Supporting). In summary, this variant meets the criteria to be classified as likely pathogenic for GENE-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP1_Strong, PM5_Supporting. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 06, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 371 of the GCK protein (p.Cys371Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with maturity-onset diabetes of the young (PMID: 19790256). ClinVar contains an entry for this variant (Variation ID: 2578347). 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%. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at