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
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!

Variant: NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr)

CA213740

36189 (ClinVar)

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: fa69a74e-6d24-423d-a24e-3ea3241ed013

HGVS expressions

NM_000162.5:c.1268T>A
NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr)
NC_000007.14:g.44145266A>T
CM000669.2:g.44145266A>T
NC_000007.13:g.44184865A>T
CM000669.1:g.44184865A>T
NC_000007.12:g.44151390A>T
NG_008847.1:g.49158T>A
NG_008847.2:g.57905T>A
ENST00000395796.8:c.*1266T>A
ENST00000616242.5:c.*388T>A
ENST00000683378.1:n.494T>A
ENST00000336642.9:c.302T>A
ENST00000345378.7:c.1271T>A
ENST00000403799.8:c.1268T>A
ENST00000671824.1:c.1331T>A
ENST00000672743.1:n.280T>A
ENST00000673284.1:c.1268T>A
ENST00000336642.8:c.320T>A
ENST00000345378.6:c.1271T>A
ENST00000395796.7:c.1265T>A
ENST00000403799.7:c.1268T>A
ENST00000437084.1:c.1217T>A
ENST00000459642.1:n.648T>A
ENST00000616242.4:c.1265T>A
NM_000162.3:c.1268T>A
NM_033507.1:c.1271T>A
NM_033508.1:c.1265T>A
NM_000162.4:c.1268T>A
NM_001354800.1:c.1268T>A
NM_001354801.1:c.257T>A
NM_001354802.1:c.128T>A
NM_001354803.1:c.302T>A
NM_033507.2:c.1271T>A
NM_033508.2:c.1265T>A
NM_033507.3:c.1271T>A
NM_033508.3:c.1265T>A
NM_001354803.2:c.302T>A

Pathogenic

Met criteria codes 6
PS4 PP3 PP2 PP4_Moderate PM2_Supporting PP1_Moderate
Not Met criteria codes 4
BA1 BS1 BP4 BP1

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.1268T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 423 (p.(Phe423Tyr)) 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 0.801, 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 eight unrelated individuals with hyperglycemia (PS4; PMIDs: 23843579, 31968686, internal lab contributors). This variant segregated with hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 28012402, 23843579). 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 with minimal increment <3 mmol/l) (PP4_Moderate; PMID: 23843579). In summary, c.1268T>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS4, PP4_Moderate, PP1_Moderate, PM2_supporting, PP2, PP3.
Met criteria codes
PS4
This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 23843579, 31968686, internal lab contributors).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.801, 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 clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6-7.6% and OGTT with minimal increment <3 mmol/l) (PP4_Moderate; PMID: 23843579).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting). absent from gnomAD v4.0.0
PP1_Moderate
This variant segregated with hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 28012402, 23843579).
Not Met criteria codes
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
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
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