chr7-44145637-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5PP2PP3PP4_ModeratePM2_Supporting
This summary comes from the ClinGen Evidence Repository: The c.1113C>G variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tryptophan at codon 371 (p.(Cys371Trp)) 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 0.891, 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 an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L and a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID:27236918; internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe), has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Cys371Trp has a greater Grantham distance. (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0 approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5 . LINK:https://erepo.genome.network/evrepo/ui/classification/CA367398928/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 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCK | NM_000162.5 | c.1113C>G | p.Cys371Trp | missense_variant | 9/10 | ENST00000403799.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCK | ENST00000403799.8 | c.1113C>G | p.Cys371Trp | missense_variant | 9/10 | 1 | NM_000162.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 04, 2021 | This variant has been observed in individual(s) with autosomal dominant maturity-onset diabetes of the young (PMID: 19790256). ClinVar contains an entry for this variant (Variation ID: 447379). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tryptophan at codon 371 of the GCK protein (p.Cys371Trp). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tryptophan. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 16, 2019 | Not found in the total gnomAD dataset, and the data is high quality (0/265258 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One de novo case with parental identity confirmed. - |
Monogenic diabetes Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | ClinGen Monogenic Diabetes Variant Curation Expert Panel | Aug 09, 2023 | The c.1113C>G variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tryptophan at codon 371 (p.(Cys371Trp)) 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 0.891, 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 an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L and a 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). This variant was identified in three unrelated individuals with a clinical picture consistent with monogenic diabetes; however, PS4_Moderate cannot be applied because this number is below the MDEP threshold (internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918; internal lab contributors). Another missense variant, c.1112G>T p.(Cys371Phe), has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Cys371Trp has a greater Grantham distance. (PM5). In summary, this variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0 approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PM5 . - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at