Variant: NM_033508.3:c.794T>C

CA367400539

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: e194105e-85ca-4f80-919e-cb4b34e67980

HGVS expressions

NM_033508.3:c.794T>C
NC_000007.14:g.44147716A>G
CM000669.2:g.44147716A>G
NC_000007.13:g.44187315A>G
CM000669.1:g.44187315A>G
NC_000007.12:g.44153840A>G
NG_008847.1:g.46708T>C
NG_008847.2:g.55455T>C
ENST00000395796.8:c.*795T>C
ENST00000616242.5:c.797T>C
ENST00000345378.7:c.800T>C
ENST00000403799.8:c.797T>C
ENST00000671824.1:c.797T>C
ENST00000673284.1:c.797T>C
ENST00000345378.6:c.800T>C
ENST00000395796.7:c.794T>C
ENST00000403799.7:c.797T>C
ENST00000437084.1:c.746T>C
ENST00000616242.4:c.794T>C
NM_000162.3:c.797T>C
NM_033507.1:c.800T>C
NM_033508.1:c.794T>C
NM_000162.4:c.797T>C
NM_001354800.1:c.797T>C
NM_033507.2:c.800T>C
NM_033508.2:c.794T>C
NM_000162.5:c.797T>C
NM_033507.3:c.800T>C

Uncertain Significance

• Met criteria codes: PM2_Supporting PP4_Moderate PP3 PP2

• Not Met criteria codes: PS4 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.797T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 266 (p.(Leu266Pro)) 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 0.975, 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 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:275059371. 24918535, internal lab contributors). One of these individuals had 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). In summary, c.797T>C 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 (specification version 1.3, approved 8/11/2023): PP2, PP3, PP4_Moderate, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• 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).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.975, 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

• PS4: This variant was identified in 2 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID:275059371, internal lab contributors).
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2023-12-02

Published on: 2023-12-02