Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
Link to SEPIO compliant JSON-LD document
  • No ClinVar Id was directly found from the curated document
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_001354803.2:c.379G>T

CA367396925

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 9ee0fda7-fd3d-421f-8118-fe441f1d98dc

HGVS expressions

NM_001354803.2:c.379G>T
NC_000007.14:g.44145189C>A
CM000669.2:g.44145189C>A
NC_000007.13:g.44184788C>A
CM000669.1:g.44184788C>A
NC_000007.12:g.44151313C>A
NG_008847.1:g.49235G>T
NG_008847.2:g.57982G>T
ENST00000395796.8:c.*1343G>T
ENST00000616242.5:c.*465G>T
ENST00000683378.1:n.571G>T
ENST00000336642.9:c.379G>T
ENST00000345378.7:c.1348G>T
ENST00000403799.8:c.1345G>T
ENST00000671824.1:c.1408G>T
ENST00000672743.1:n.357G>T
ENST00000673284.1:c.1345G>T
ENST00000336642.8:c.397G>T
ENST00000345378.6:c.1348G>T
ENST00000395796.7:c.1342G>T
ENST00000403799.7:c.1345G>T
ENST00000437084.1:c.1294G>T
ENST00000459642.1:n.725G>T
ENST00000616242.4:c.1342G>T
NM_000162.3:c.1345G>T
NM_033507.1:c.1348G>T
NM_033508.1:c.1342G>T
NM_000162.4:c.1345G>T
NM_001354800.1:c.1345G>T
NM_001354801.1:c.334G>T
NM_001354802.1:c.205G>T
NM_001354803.1:c.379G>T
NM_033507.2:c.1348G>T
NM_033508.2:c.1342G>T
NM_000162.5:c.1345G>T
NM_033507.3:c.1348G>T
NM_033508.3:c.1342G>T

Likely Pathogenic

Met criteria codes 5
PP3 PP2 PM2_Supporting PM5 PP4_Moderate
Not Met criteria codes 1
PM1

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.1345G>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to serine at codon 449 (p.(Ala449Ser)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.878, 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 negative antibodies and 3-generation family history of diabetes) (PP4_Moderate; PMID: 19410318). Another missense variant, c.1345G>A p.Ala449Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala449Ser has a greater Grantham distance (PM5). In summary, c.1345G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PM5, PP2, PP3, PM2_Supporting.
Met criteria codes
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.878, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
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).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Absent from gnomAD v4.0.
PM5
Another missense variant, c.1345G>A p.Ala449Thr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Ala449Ser has a greater Grantham distance (PM5).
PP4_Moderate
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 negative antibodies and 3-generation family history of diabetes) (PP4_Moderate; PMID: 19410318).
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2024-04-27
Published on: 2024-04-27
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.