Variant: NM_001354803.2:c.133G>T

CA367398995

1802685 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 31b7612e-7a2b-4312-bf85-1b228a05819f

HGVS expressions

NM_001354803.2:c.133G>T
NC_000007.14:g.44145651C>A
CM000669.2:g.44145651C>A
NC_000007.13:g.44185250C>A
CM000669.1:g.44185250C>A
NC_000007.12:g.44151775C>A
NG_008847.1:g.48773G>T
NG_008847.2:g.57520G>T
ENST00000395796.8:c.*1097G>T
ENST00000616242.5:c.*219G>T
ENST00000683378.1:n.325G>T
ENST00000336642.9:c.133G>T
ENST00000345378.7:c.1102G>T
ENST00000403799.8:c.1099G>T
ENST00000671824.1:c.1162G>T
ENST00000672743.1:n.111G>T
ENST00000673284.1:c.1099G>T
ENST00000336642.8:n.151G>T
ENST00000345378.6:c.1102G>T
ENST00000395796.7:c.1096G>T
ENST00000403799.7:c.1099G>T
ENST00000437084.1:c.1048G>T
ENST00000459642.1:n.479G>T
ENST00000473353.1:n.397G>T
ENST00000616242.4:n.1096G>T
NM_000162.3:c.1099G>T
NM_033507.1:c.1102G>T
NM_033508.1:c.1096G>T
NM_000162.4:c.1099G>T
NM_001354800.1:c.1099G>T
NM_001354801.1:c.88G>T
NM_001354802.1:c.-42G>T
NM_001354803.1:c.133G>T
NM_033507.2:c.1102G>T
NM_033508.2:c.1096G>T
NM_000162.5:c.1099G>T
NM_033507.3:c.1102G>T
NM_033508.3:c.1096G>T
NM_000162.5(GCK):c.1099G>T (p.Val367Leu)

Uncertain Significance

• Met criteria codes: PP3 PP2 PM5 PM2_Supporting

• Not Met criteria codes: PP4

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1099G>T variant in the glucokinase gene, GCK, causes an amino acid change of valine to leucine at codon 367 (p.(Val367Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.813, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.1099G>A p.(Val367Met), has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Val367Leu has a greater Grantham distance (PM5). This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0 approved 6/7/2023): PP2, PP3, PM2_Supporting, PM5.

Met criteria codes

• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.813, 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).
• PM5: Another missense variant, c.1099G>A p.(Val367Met) has been interpreted as pathogenic by the ClinGen MDEP VCEP and p.Val367Leu has a greater Grantham distance. (PM5).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PP4: This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors).

Approved on: 2023-08-09

Published on: 2023-08-10