The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!


Variant: NM_033508.3:c.673G>C

CA367401125

2691832 (ClinVar)

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
UUID: 7b1e5910-73fc-4465-bcee-10f3ce0687bb
Approved on: 2024-02-02
Published on: 2024-02-02

HGVS expressions

NM_033508.3:c.673G>C
NC_000007.14:g.44149763C>G
CM000669.2:g.44149763C>G
NC_000007.13:g.44189362C>G
CM000669.1:g.44189362C>G
NC_000007.12:g.44155887C>G
NG_008847.1:g.44661G>C
NG_008847.2:g.53408G>C
ENST00000395796.8:c.*674G>C
ENST00000616242.5:c.676G>C
ENST00000682635.1:n.1162G>C
ENST00000345378.7:c.679G>C
ENST00000403799.8:c.676G>C
ENST00000671824.1:c.676G>C
ENST00000673284.1:c.676G>C
ENST00000345378.6:c.679G>C
ENST00000395796.7:c.673G>C
ENST00000403799.7:c.676G>C
ENST00000437084.1:c.625G>C
ENST00000616242.4:c.673G>C
NM_000162.3:c.676G>C
NM_033507.1:c.679G>C
NM_033508.1:c.673G>C
NM_000162.4:c.676G>C
NM_001354800.1:c.676G>C
NM_033507.2:c.679G>C
NM_033508.2:c.673G>C
NM_000162.5:c.676G>C
NM_033507.3:c.679G>C
More

Uncertain Significance

Met criteria codes 4
PP2 PM1 PM5_Supporting PM2_Supporting
Not Met criteria codes 2
PP3 PP4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.676G>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 226 (p.(Val226leu)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). 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 absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting). This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 21348868). In summary, c.676G>C meets the criteria to be classified as a variant of uncertain signficance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM1, PP2, PM2_Supporting, PM5_Supporting.
Met criteria codes
PP2
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).
PM1
This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).
PM5_Supporting
Another missense variant, c.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Leu (PM5_Supporting).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
Not Met criteria codes
PP3
This variant has a REVEL score of 0.667 which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.
PP4
This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (PMID: 21348868).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.