Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000162.5(GCK):c.679+2T>C

CA367401107

3768773 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: d5bd8645-769e-4843-86fc-400038206ca3

Approved on: 2025-09-17

Published on: 2025-09-26

HGVS expressions

NM_000162.5:c.679+2T>C

NM_000162.5(GCK):c.679+2T>C

NC_000007.14:g.44149758A>G

CM000669.2:g.44149758A>G

NC_000007.13:g.44189357A>G

CM000669.1:g.44189357A>G

NC_000007.12:g.44155882A>G

NG_008847.1:g.44666T>C

NG_008847.2:g.53413T>C

ENST00000395796.8:c.*677+2T>C

ENST00000616242.5:c.679+2T>C

ENST00000682635.1:n.1167T>C

ENST00000345378.7:c.682+2T>C

ENST00000403799.8:c.679+2T>C

ENST00000671824.1:c.679+2T>C

ENST00000673284.1:c.679+2T>C

ENST00000345378.6:c.682+2T>C

ENST00000395796.7:c.676+2T>C

ENST00000403799.7:c.679+2T>C

ENST00000437084.1:c.628+2T>C

ENST00000616242.4:c.676+2T>C

NM_000162.3:c.679+2T>C

NM_033507.1:c.682+2T>C

NM_033508.1:c.676+2T>C

NM_000162.4:c.679+2T>C

NM_001354800.1:c.679+2T>C

NM_033507.2:c.682+2T>C

NM_033508.2:c.676+2T>C

NM_033507.3:c.682+2T>C

NM_033508.3:c.676+2T>C

Pathogenic

PS4_Moderate PP4_Moderate PVS1 PM2_Supporting PS1_Supporting PP1_Strong

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.679+2T>C 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 was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors). Additionally, one of these individuals had a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, antibody negative) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with four informative meioses in three families (PP1_Strong; internal lab contributors). Another variant within same splice donor ±1,2 dinucleotide, c.679+1G>T, has been classified as pathogenic by the ClinGen MDEP, and both variants have the same predicted impact on splicing by SpliceAI (0.99) (PS1_Supporting). In summary, c.679+2T>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.0.0, approved 7/23/2025): PVS1, PP1_Strong, PS4_Moderate, PP4_Moderate, PM2_Supporting, PS1_Supporting.

PS4_Moderate

This variant was identified in five unrelated individuals with hyperglycemia (PS4_Moderate; internal lab contributors).

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 autoantibodies) (PP4_Moderate; internal lab contributors).

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).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PS1_Supporting

Another variant within same splice donor ±1,2 dinucleotide, c.679+1G>T, has been classified as pathogenic by the ClinGen MDEP, and both variants have the same predicted impact on splicing by SpliceAI (0.99) (PS1_Supporting).

PP1_Strong

This variant segregated with hyperglycemia with four informative meioses in three families (PP1_Strong; internal lab contributors).

Curation History

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