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.704T>C (p.Met235Thr)

CA213834

36248 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: e65ee788-cb00-4d36-b41c-e4e537d41002

Approved on: 2025-09-17

Published on: 2025-09-26

HGVS expressions

NM_000162.5(GCK):c.704T>C (p.Met235Thr)

NM_000162.5:c.704T>C

NC_000007.14:g.44147809A>G

CM000669.2:g.44147809A>G

NC_000007.13:g.44187408A>G

CM000669.1:g.44187408A>G

NC_000007.12:g.44153933A>G

NG_008847.1:g.46615T>C

NG_008847.2:g.55362T>C

ENST00000395796.8:c.*702T>C

ENST00000616242.5:c.704T>C

ENST00000345378.7:c.707T>C

ENST00000403799.8:c.704T>C

ENST00000671824.1:c.704T>C

ENST00000673284.1:c.704T>C

ENST00000345378.6:c.707T>C

ENST00000395796.7:c.701T>C

ENST00000403799.7:c.704T>C

ENST00000437084.1:c.653T>C

ENST00000616242.4:c.701T>C

NM_000162.3:c.704T>C

NM_033507.1:c.707T>C

NM_033508.1:c.701T>C

NM_000162.4:c.704T>C

NM_001354800.1:c.704T>C

NM_033507.2:c.707T>C

NM_033508.2:c.701T>C

NM_033507.3:c.707T>C

NM_033508.3:c.701T>C

Pathogenic

PM5 PP1_Strong PS3_Moderate PS4 PM2_Supporting PP3 PP2 PP4_Moderate

PM1

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.704T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 235 (p.(Met235Thr)) 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 has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting. This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Additionally, MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.21, which is below the MDEP cutoff (<0.5) (PS3_Moderate; Gloyn et al., 2004 (DOI: 10.1159/000079009)). This variant has been indentified in at least 43 individuals with hyperglycemia (PS4; PMID: 19564454, 30592380; internal lab contributors). Furthermore, this variant segregated with hyperglycemia with at least 11 meioses in multiple families (PP1_Strong; internal lab contributors). At least 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% and negative autoantibodies) (PP4_Moderate; internal lab contributors). Another missense variant at the same residue, c.703A>G (p.Met235Val), has been classified as pathogenic by the ClinGen MDEP and p.Met235Thr has a greater Grantham distance (PM5). In summary, c.704T>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): PS4, PP1_Strong, PS3_Moderate, PP4_Moderate, PM5, PM2_Supporting, PP2, PP3.

PM5

Another missense variant at the same residue, c.703A>G (p.Met235Val), has been classified as pathogenic by the ClinGen MDEP and p.Met235Thr has a greater Grantham distance (PM5).

PP1_Strong

This variant segregated with hyperglycemia with at least 11 meioses in multiple families (PP1_Strong; internal lab contributors).

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.21, which is below the MDEP cutoff (<0.5) (PS3_Moderate; Gloyn et al., 2004 (DOI: 10.1159/000079009)).

PS4

This variant has been indentified in at least 43 individuals with hyperglycemia (PS4; PMID: 19564454, 30592380; internal lab contributors)

PM2_Supporting

This variant has an incomputable gnomAD v4.1.0 Grpmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.969, 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).

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).

PM1

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Curation History

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