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]
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Variant: NM_000162.5(GCK):c.622G>A (p.Ala208Thr)

CA367401322

804344 (ClinVar)

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 7be4b009-9f38-4314-9c03-e3d5facd3f2d

HGVS expressions

NM_000162.5:c.622G>A
NM_000162.5(GCK):c.622G>A (p.Ala208Thr)
NC_000007.14:g.44149817C>T
CM000669.2:g.44149817C>T
NC_000007.13:g.44189416C>T
CM000669.1:g.44189416C>T
NC_000007.12:g.44155941C>T
NG_008847.1:g.44607G>A
NG_008847.2:g.53354G>A
ENST00000395796.8:c.*620G>A
ENST00000616242.5:c.622G>A
ENST00000682635.1:n.1108G>A
ENST00000345378.7:c.625G>A
ENST00000403799.8:c.622G>A
ENST00000671824.1:c.622G>A
ENST00000673284.1:c.622G>A
ENST00000345378.6:c.625G>A
ENST00000395796.7:c.619G>A
ENST00000403799.7:c.622G>A
ENST00000437084.1:c.571G>A
ENST00000616242.4:c.619G>A
NM_000162.3:c.622G>A
NM_033507.1:c.625G>A
NM_033508.1:c.619G>A
NM_000162.4:c.622G>A
NM_001354800.1:c.622G>A
NM_033507.2:c.625G>A
NM_033508.2:c.619G>A
NM_033507.3:c.625G>A
NM_033508.3:c.619G>A

Pathogenic

Met criteria codes 9
PP1_Moderate PM3_Supporting PS4_Moderate PM2_Supporting PS3_Moderate PM5_Supporting PP3 PP2 PP4_Moderate

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.622G>A variant in the glucokinase gene, GCK causes an amino acid change of Ala to Thr at codon 210 (p.(Ala208Thr)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.905, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an uncomputable Popmax filtering allele frequency in the gnomAD v2.1.1 due to only one copy in the European non-Finnish population and no copies in another subpopulation (PM2_Supporting). This variant was identified in the heterozygous state in 4 unrelated individuals with diabetes/hyperglycemia (PS4; PMID: internal lab contributors). This variant has been detected in the homozygous state in an Individual with permanent neonatal diabetes (PM3_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; internal lab contributors). This variant segregated with diabetes/hyperglycemia with 3 informative meioses in 2 families (PP1_Strong; PMID 25015100; internal lab contributors). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Ala208Thr has RAI<0.50 (PS3_Moderate; PMID: 25015100). Another missense variant, c.623C>T p.Ala208Val, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala208Thr (PM5_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3, approved 8/11/2023) PP3, PP2, PM2_Supporting, PP4_Moderate, PM5_Supporting, PS4_Moderate, PM3_Supporting, PP1_Moderate, PS3_Moderate.
Met criteria codes
PP1_Moderate
This variant segregated with diabetes with 3 informative meioses in 2 families (PP1_Strong; PMID 25015100; internal lab contributors).
PM3_Supporting
This variant has been detected in the homozygous state in an Individual with permanent neonatal diabetes (PM3_Supporting).
PS4_Moderate
This variant was identified in the heterozygous state in 4 unrelated individuals with diabetes/hyperglycemia (PS4; PMID: internal lab contributors).
PM2_Supporting
This variant has an uncomputable Popmax filtering allele frequency in the gnomAD v2.1.1 due to only one copy in the European non-Finnish population and no copies in another subpopulation (PM2_Supporting).
PS3_Moderate
A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Ala208Thr has RAI<0.50 (PS3_Moderate; PMID: 25015100).
PM5_Supporting
Another missense variant, c.623C>T p.Ala208Val, has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Ala208Thr. (PM5_Supporting).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.905, 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-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3.0 mmol/L) (PP4_Moderate; internal lab contributors).
Approved on: 2024-05-12
Published on: 2024-05-12
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