Variant: NM_033508.3:c.676+3A>T

Version: 2.0
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CA2529312623

2691831 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: fd93be23-8465-44a6-8548-1808e7aa4fc1

Approved on: 2025-09-17

Published on: 2025-09-26

HGVS expressions

NM_033508.3:c.676+3A>T
NC_000007.14:g.44149757T>A
CM000669.2:g.44149757T>A
NC_000007.13:g.44189356T>A
CM000669.1:g.44189356T>A
NC_000007.12:g.44155881T>A
NG_008847.1:g.44667A>T
NG_008847.2:g.53414A>T
ENST00000395796.8:c.*677+3A>T
ENST00000616242.5:c.679+3A>T
ENST00000682635.1:n.1168A>T
ENST00000345378.7:c.682+3A>T
ENST00000403799.8:c.679+3A>T
ENST00000671824.1:c.679+3A>T
ENST00000673284.1:c.679+3A>T
ENST00000345378.6:c.682+3A>T
ENST00000395796.7:c.676+3A>T
ENST00000403799.7:c.679+3A>T
ENST00000437084.1:c.628+3A>T
ENST00000616242.4:c.676+3A>T
NM_000162.3:c.679+3A>T
NM_033507.1:c.682+3A>T
NM_033508.1:c.676+3A>T
NM_000162.4:c.679+3A>T
NM_001354800.1:c.679+3A>T
NM_033507.2:c.682+3A>T
NM_033508.2:c.676+3A>T
NM_000162.5:c.679+3A>T
NM_033507.3:c.682+3A>T

Likely Pathogenic

• Met criteria codes: PP4_Moderate PS1_Moderate PP3 PM2_Supporting

• Not Met criteria codes: PS4

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 3.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.679+3A>T variant in the glucokinase gene, GCK, is a noncanonical splice donor site variant in intron 6 of NM_000162.5. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational splicing predictor SpliceAI gives a score of 0.87 for donor loss, predicting that the variant disrupts the donor site of intron 6 of GCK (PP3). 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% and negative antibodies) (PP4_Moderate; internal lab contributors). Additionally, other variants within the same splice donor motif, c.679+5G>A and c.679+5G>C, have been classified as pathogenic by the ClinGen MDEP and c.679+3A>T has a greater predicted deleterious impact by SpliceAI (0.87 vs. 0.26 and 0.43, respectively) (PS1_Moderate). In summary, c.679+3A>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PS1_Moderate, PP4_Moderate, PP3, PM2_Supporting.

Met criteria codes

• 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% and negative antibodies) (PP4_Moderate; internal lab contributors).
• PS1_Moderate: Other variants within the same splice donor motif, c.679+5G>A and c.679+5G>C, have been classified as pathogenic by the ClinGen MDEP and c.679+3A>T has a greater predicted deleterious impact by SpliceAI (0.87 vs. 0.26 and 0.43, respectively) (PS1_Moderate).
• PP3: The computational splicing predictor SpliceAI gives a score of 0.87 for donor loss, predicting that the variant disrupts the donor site of intron 6 of GCK (PP3).
• PM2_Supporting: This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

Not Met criteria codes

• PS4: .