Variant: NM_033508.3:c.676+1G>T

CA367401109

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 0497675e-d350-4bb6-9702-e76f227b4b93

Approved on: 2025-06-27

Published on: 2025-06-27

HGVS expressions

NM_033508.3:c.676+1G>T
NC_000007.14:g.44149759C>A
CM000669.2:g.44149759C>A
NC_000007.13:g.44189358C>A
CM000669.1:g.44189358C>A
NC_000007.12:g.44155883C>A
NG_008847.1:g.44665G>T
NG_008847.2:g.53412G>T
ENST00000395796.8:c.*677+1G>T
ENST00000616242.5:c.679+1G>T
ENST00000682635.1:n.1166G>T
ENST00000345378.7:c.682+1G>T
ENST00000403799.8:c.679+1G>T
ENST00000671824.1:c.679+1G>T
ENST00000673284.1:c.679+1G>T
ENST00000345378.6:c.682+1G>T
ENST00000395796.7:c.676+1G>T
ENST00000403799.7:c.679+1G>T
ENST00000437084.1:c.628+1G>T
ENST00000616242.4:c.676+1G>T
NM_000162.3:c.679+1G>T
NM_033507.1:c.682+1G>T
NM_033508.1:c.676+1G>T
NM_000162.4:c.679+1G>T
NM_001354800.1:c.679+1G>T
NM_033507.2:c.682+1G>T
NM_033508.2:c.676+1G>T
NM_000162.5:c.679+1G>T
NM_033507.3:c.682+1G>T

Pathogenic

• Met criteria codes: PM3 PM2_Supporting PVS1 PP4_Moderate

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 2.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.679+1G>T variant in glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 6 of transcript NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 6 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in an individual with neonatal diabetes in a compound heterozygous state with another variant (c.676G>A) classified as pathogenic by ClinGen MDEP, and these variants were confirmed in trans (internal lab contributors) (PM3). This variant was also identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative, and a 3-generation dominant family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, c.679+1G>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 2.0.0, approved 02/17/2025): PVS1, PM3, PP4_Moderate, PM2_Supporting

Met criteria codes

• PM3: This variant has been detected in an individual with neonatal diabetes in a compound heterozygous state with another variant (c.676G>A) classified as pathogenic by ClinGen MDEP, and these variants were confirmed in trans (internal lab contributors) (PM3).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
• PVS1: This variant is predicted to cause skipping of biologically-relevant exon 6 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256).
• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative, and a 3-generation dominant family history of diabetes) (PP4_Moderate; internal lab contributors).