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]
  • 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_000162.5(GCK):c.1264C>T (p.Arg422Trp)

CA367397271

1700675 (ClinVar)

Gene: GCK (HGNC:2645)
Condition: monogenic diabetes (MONDO:0015967)
Inheritance Mode: Semidominant inheritance
UUID: 6b0135a9-3845-4df1-a393-598775a2b89c
Approved on: 2026-09-21
Published on: 2026-09-29

HGVS expressions

NM_000162.5(GCK):c.1264C>T (p.Arg422Trp)
NM_000162.5:c.1264C>T
NC_000007.14:g.44145270G>A
CM000669.2:g.44145270G>A
NC_000007.13:g.44184869G>A
CM000669.1:g.44184869G>A
NC_000007.12:g.44151394G>A
NG_008847.1:g.49154C>T
NG_008847.2:g.57901C>T
ENST00000395796.8:c.*1262C>T
ENST00000616242.5:c.*384C>T
ENST00000683378.1:n.490C>T
ENST00000336642.9:c.298C>T
ENST00000345378.7:c.1267C>T
ENST00000403799.8:c.1264C>T
ENST00000671824.1:c.1327C>T
ENST00000672743.1:n.276C>T
ENST00000673284.1:c.1264C>T
ENST00000336642.8:c.316C>T
ENST00000345378.6:c.1267C>T
ENST00000395796.7:c.1261C>T
ENST00000403799.7:c.1264C>T
ENST00000437084.1:c.1213C>T
ENST00000459642.1:n.644C>T
ENST00000616242.4:c.1261C>T
NM_000162.3:c.1264C>T
NM_033507.1:c.1267C>T
NM_033508.1:c.1261C>T
NM_000162.4:c.1264C>T
NM_001354800.1:c.1264C>T
NM_001354801.1:c.253C>T
NM_001354802.1:c.124C>T
NM_001354803.1:c.298C>T
NM_033507.2:c.1267C>T
NM_033508.2:c.1261C>T
NM_033507.3:c.1267C>T
NM_033508.3:c.1261C>T
NM_001354803.2:c.298C>T
More

Likely Pathogenic

Met criteria codes 5
PP3 PP2 PP4_Moderate PM2_Supporting PM5_Supporting
Not Met criteria codes 2
PM1 PS4

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 3.1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.1264C>T variant in the glucokinase, GCK, causes an amino acid change of arginine to tryptophan at codon 422 (p.Arg422Trp) 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 0.758, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 0.00000183, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, this number is below the ClinGen MDEP threshold for PS4_Moderate (PMID: 36257325, internal lab contributors). At least one of these individuals had a phenotype highly consistent for GCK-related hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors). Another missense variant at the same residue, c.1265G>C (p.Arg422Pro), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1264C>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 3.1, approved 10/10/2025): PP4_Moderate, PM2_Supporting, PM5_Supporting, PP2, PP3.
Met criteria codes
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.758, 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).
PP4_Moderate
This variant was identified in an individual with a phenotype highly consistent for GCK-related hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate, internal lab contributors).
PM2_Supporting
This variant has a gnomAD v4.1.0 Grpmax filtering allele frequency of 0.00000183, which is below the ClinGen MDEP threshold of 0.000003 (PM2_Supporting).
PM5_Supporting
Another missense variant at the same residue, c.1265G>C (p.Arg422Pro), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
This variant was identified in three unrelated individuals with hyperglycemia; however, this number is below the ClinGen MDEP threshold for PS4_Moderate (PMID: 36257325, internal lab contributors).
Curation History
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