Variant: NM_000162.5(GCK):c.790G>A (p.Gly264Ser)

CA341589

21078 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: a0bd4d0f-fd6d-43b1-b64a-12ff1f71245d

Approved on: 2023-11-02

Published on: 2023-11-02

HGVS expressions

NM_000162.5:c.790G>A
NM_000162.5(GCK):c.790G>A (p.Gly264Ser)
NC_000007.14:g.44147723C>T
CM000669.2:g.44147723C>T
NC_000007.13:g.44187322C>T
CM000669.1:g.44187322C>T
NC_000007.12:g.44153847C>T
NG_008847.1:g.46701G>A
NG_008847.2:g.55448G>A
ENST00000395796.8:c.*788G>A
ENST00000616242.5:c.790G>A
ENST00000345378.7:c.793G>A
ENST00000403799.8:c.790G>A
ENST00000671824.1:c.790G>A
ENST00000673284.1:c.790G>A
ENST00000345378.6:c.793G>A
ENST00000395796.7:c.787G>A
ENST00000403799.7:c.790G>A
ENST00000437084.1:c.739G>A
ENST00000616242.4:c.787G>A
NM_000162.3:c.790G>A
NM_033507.1:c.793G>A
NM_033508.1:c.787G>A
NM_000162.4:c.790G>A
NM_001354800.1:c.790G>A
NM_033507.2:c.793G>A
NM_033508.2:c.787G>A
NM_033507.3:c.793G>A
NM_033508.3:c.787G>A

Pathogenic

• Met criteria codes: PM3_Strong PS4 PP3 PP2 PP1_Strong PP4_Moderate PM2_Supporting

• Not Met criteria codes: PS3 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.790G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to serine at codon 264 (p.(Gly264Ser)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 11508276, 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). This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; PMID: 16026363s, internal lab contributors). This variant has been detected in two individuals with neonatal diabetes. Both were compound heterozygous (confirmed in trans) for this variant and another variant classified as pathogenic by ClinGen MDEP (PM3_Strong; PMIDs: 14578306, 16026363, 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 0.847, which is greater than the MDEP VCEP threshold of 0.70 (PP3). The Relative Activity Index (RAI) of this variant was found to be above the MDEP cutoff (0.5) for PS3_Moderate. While the p.Gly264Ser variant has been reported to cause protein misfolding, this is not considered to meet criteria for applying PS3_Supporting by the ClinGen MDEP (PMIDs: 22820548, 14578306, 16731834, https://doi.org/10.1159/000079009). In summary, c.790G>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, PM3_Strong, PP2, PP3, PM2_Supporting.

Met criteria codes

• PM3_Strong: This variant has been detected in two individuals with neonatal diabetes. Both were compound heterozygous (confirmed in trans) for this variant and another variant classified as pathogenic by ClinGen MDEP (PM3_Strong; PMIDs: 14578306, 16026363, internal lab contributors).
• PS4: This variant was identified in 7 unrelated individuals with hyperglycemia (PS4; PMID: 11508276, internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.847, 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).
• PP1_Strong: This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; PMID: 16026363s, 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) (internal lab contributors).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS3: The Relative Activity Index (RAI) of this variant was found to be above the MDEP cutoff (0.5) for PS3_Moderate. While the p.Gly264Ser variant has been reported to cause protein misfolding, this is not considered to meet criteria for applying PS3_Supporting by the ClinGen MDEP (PMIDs: 22820548, 14578306, 16731834, https://doi.org/10.1159/000079009).
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline