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

CA4239418

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 394c4cf8-a31d-49a4-bfb7-d807da3723a6

HGVS expressions

NM_001354803.2:c.223C>T
NC_000007.14:g.44145561G>A
CM000669.2:g.44145561G>A
NC_000007.13:g.44185160G>A
CM000669.1:g.44185160G>A
NC_000007.12:g.44151685G>A
NG_008847.1:g.48863C>T
NG_008847.2:g.57610C>T
ENST00000395796.8:c.*1187C>T
ENST00000616242.5:c.*309C>T
ENST00000683378.1:n.415C>T
ENST00000336642.9:c.223C>T
ENST00000345378.7:c.1192C>T
ENST00000403799.8:c.1189C>T
ENST00000671824.1:c.1252C>T
ENST00000672743.1:n.201C>T
ENST00000673284.1:c.1189C>T
ENST00000336642.8:n.241C>T
ENST00000345378.6:c.1192C>T
ENST00000395796.7:c.1186C>T
ENST00000403799.7:c.1189C>T
ENST00000437084.1:c.1138C>T
ENST00000459642.1:n.569C>T
ENST00000616242.4:n.1186C>T
NM_000162.3:c.1189C>T
NM_033507.1:c.1192C>T
NM_033508.1:c.1186C>T
NM_000162.4:c.1189C>T
NM_001354800.1:c.1189C>T
NM_001354801.1:c.178C>T
NM_001354802.1:c.49C>T
NM_001354803.1:c.223C>T
NM_033507.2:c.1192C>T
NM_033508.2:c.1186C>T
NM_000162.5:c.1189C>T
NM_033507.3:c.1192C>T
NM_033508.3:c.1186C>T

Likely Pathogenic

Met criteria codes 6
PM5 PS4_Moderate PM2_Supporting PP4 PP3 PP2

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 1.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.1189C>T variant in the glucokinase gene, GCK, causes an amino acid change of arginine to cysteine at codon 397 (p.(Arg397Cys)) 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). Additionally, this variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, 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 4 unrelated individuals with hyperglycemia (PS4_Moderate, internal lab contributors). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). Additionally, another missense variant, c.1190G>T p.(Arg397Leu) has been interpreted as pathogenic by the ClinGen MDEP and p.Arg397Cys has a greater Grantham distance. (PM5). Taken together, this evidence supports the classification of this variant 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): PM5, PP2, PP3, PS4_Moderate, PP4, PM2_Supporting.
Met criteria codes
PM5
Another missense variant, c.1190G>T p.(Arg397Leu) has been interpreted as pathogenic by the ClinGen MDEP and p.Arg397Cys has a greater Grantham distance (PM5).
PS4_Moderate
This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PP4
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%) (PP4; internal lab contributors).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.886, 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)
Approved on: 2023-09-08
Published on: 2023-09-08
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