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Variant: NM_000162.5(GCK):c.604A>G (p.Met202Val)

CA213808

36232 (ClinVar)

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
UUID: 48fe1cbc-13fb-4e6b-ab56-28547a8845a5

HGVS expressions

NM_000162.5:c.604A>G
NM_000162.5(GCK):c.604A>G (p.Met202Val)
NC_000007.14:g.44149835T>C
CM000669.2:g.44149835T>C
NC_000007.13:g.44189434T>C
CM000669.1:g.44189434T>C
NC_000007.12:g.44155959T>C
NG_008847.1:g.44589A>G
NG_008847.2:g.53336A>G
ENST00000395796.8:c.*602A>G
ENST00000616242.5:c.604A>G
ENST00000682635.1:n.1090A>G
ENST00000345378.7:c.607A>G
ENST00000403799.8:c.604A>G
ENST00000671824.1:c.604A>G
ENST00000673284.1:c.604A>G
ENST00000345378.6:c.607A>G
ENST00000395796.7:c.601A>G
ENST00000403799.7:c.604A>G
ENST00000437084.1:c.553A>G
ENST00000616242.4:c.601A>G
NM_000162.3:c.604A>G
NM_033507.1:c.607A>G
NM_033508.1:c.601A>G
NM_000162.4:c.604A>G
NM_001354800.1:c.604A>G
NM_033507.2:c.607A>G
NM_033508.2:c.601A>G
NM_033507.3:c.607A>G
NM_033508.3:c.601A>G

Uncertain Significance

Met criteria codes 4
PM5_Supporting PM2_Supporting PP2 PP4_Moderate
Not Met criteria codes 3
PS4 PP1 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.604A>G variant in the glucokinase gene, GCK, causes an amino acid change of methionine to valine at codon 202 (p.(Met202Val)) 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 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 persistent impaired fasting glucose) (PP4_Moderate; internal lab contributors). Another missense variant, c.605T>C p.Met202Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met202Val (PM5_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors). This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors). This variant has a REVEL score of 0.596, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. In summary, c.604A>G meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM2_Supporting, PM5_Supporting, PP2, PP4_Moderate.
Met criteria codes
PM5_Supporting
Another missense variant, c.605T>C p.Met202Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met202Val (PM5_Supporting).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
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 persistent impaired fasting glucose) (PP4_Moderate; internal lab contributors).
Not Met criteria codes
PS4
This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (ClinVar, internal lab contributors).
PP1
This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributors).
PP3
This variant has a REVEL score of 0.596, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function.
Approved on: 2024-02-19
Published on: 2024-02-19
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