Variant: NM_000162.5(GCK):c.802G>A (p.Glu268Lys)

CA367400529

447420 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 93ccf57a-26e5-4877-90ce-0e0474dc8231

Approved on: 2023-10-05

Published on: 2023-10-05

HGVS expressions

NM_000162.5:c.802G>A
NM_000162.5(GCK):c.802G>A (p.Glu268Lys)
NC_000007.14:g.44147711C>T
CM000669.2:g.44147711C>T
NC_000007.13:g.44187310C>T
CM000669.1:g.44187310C>T
NC_000007.12:g.44153835C>T
NG_008847.1:g.46713G>A
NG_008847.2:g.55460G>A
ENST00000395796.8:c.*800G>A
ENST00000616242.5:c.802G>A
ENST00000345378.7:c.805G>A
ENST00000403799.8:c.802G>A
ENST00000671824.1:c.802G>A
ENST00000673284.1:c.802G>A
ENST00000345378.6:c.805G>A
ENST00000395796.7:c.799G>A
ENST00000403799.7:c.802G>A
ENST00000437084.1:c.751G>A
ENST00000616242.4:c.799G>A
NM_000162.3:c.802G>A
NM_033507.1:c.805G>A
NM_033508.1:c.799G>A
NM_000162.4:c.802G>A
NM_001354800.1:c.802G>A
NM_033507.2:c.805G>A
NM_033508.2:c.799G>A
NM_033507.3:c.805G>A
NM_033508.3:c.799G>A

Pathogenic

• Met criteria codes: PP1_Strong PP4_Moderate PM2_Supporting PS4 PP3 PP2

• Not Met criteria codes: PM1

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 1.3.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.802G>A variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to lysine at codon 268 (p.(Glu268Lys)) of NM_000162.5. This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families (PP1_Strong; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; internal lab contributors). 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 negative antibodies) (PP4_Moderate; internal lab contributors). 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 0.727, which is greater than the MDEP VCEP threshold of 0.70 (PP3). In summary, c.802G>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): PP1_Strong, PS4, PP4_Moderate, PP2, PP3, PM2_Supporting.

Met criteria codes

• PP1_Strong: This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families (PP1_Strong; internal lab contributors).
• 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 negative antibodies) (PP4_Moderate; internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS4: This variant was identified in 8 unrelated individuals with hyperglycemia (PS4; internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.727, 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).

Not Met criteria codes

• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline