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_001354803.2:c.208C>A

CA367398628

2581305 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 9aafc77f-1c7a-4e68-8657-248772693e8d

Approved on: 2025-11-26

Published on: 2025-11-26

HGVS expressions

NM_001354803.2:c.208C>A

NC_000007.14:g.44145576G>T

CM000669.2:g.44145576G>T

NC_000007.13:g.44185175G>T

CM000669.1:g.44185175G>T

NC_000007.12:g.44151700G>T

NG_008847.1:g.48848C>A

NG_008847.2:g.57595C>A

ENST00000395796.8:c.*1172C>A

ENST00000616242.5:c.*294C>A

ENST00000683378.1:n.400C>A

ENST00000336642.9:c.208C>A

ENST00000345378.7:c.1177C>A

ENST00000403799.8:c.1174C>A

ENST00000671824.1:c.1237C>A

ENST00000672743.1:n.186C>A

ENST00000673284.1:c.1174C>A

ENST00000336642.8:c.226C>A

ENST00000345378.6:c.1177C>A

ENST00000395796.7:c.1171C>A

ENST00000403799.7:c.1174C>A

ENST00000437084.1:c.1123C>A

ENST00000459642.1:n.554C>A

ENST00000616242.4:c.1171C>A

NM_000162.3:c.1174C>A

NM_033507.1:c.1177C>A

NM_033508.1:c.1171C>A

NM_000162.4:c.1174C>A

NM_001354800.1:c.1174C>A

NM_001354801.1:c.163C>A

NM_001354802.1:c.34C>A

NM_001354803.1:c.208C>A

NM_033507.2:c.1177C>A

NM_033508.2:c.1171C>A

NM_000162.5:c.1174C>A

NM_033507.3:c.1177C>A

NM_033508.3:c.1171C>A

Pathogenic

PM2_Supporting PM5_Strong PP1 PP3 PP2 PS3_Supporting PP4_Moderate

PS4

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1174C>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to serine at codon 392 (p.(Arg392Ser)) 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 is predicted to be deleterious by computational evidence, with a REVEL score of 0.778, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18382660, internal lab contributors). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and antibody negative) (PP4_Moderate; PMID: 18382660). This variant segregated with hyperglycemia, with two informative meioses in two families (PP1; PMID: 18382660, internal lab contributors). While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, the relative stability index was below the MDEP cutoff of 0.5 (PS3_Supporting; PMID: 22761713). Two other missense variants at the same amino acid position, c.1174C>T p.(Arg392Cys) and c.1175G>T p.(Arg392Leu), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.1174C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0 approved 10/10/2025): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_Strong, PS3_Supporting, PP1.

PM2_Supporting

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

PM5_Strong

Two other missense variants at the same amino acid position, c.1174C>T p.(Arg392Cys) and c.1175G>T p.(Arg392Leu), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong).

PP1

This variant segregated with hyperglycemia, with two informative meioses in two families (PP1; PMID: 18382660, internal lab contributors)

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.778, 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).

PS3_Supporting

While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, the relative stability index was below the MDEP cutoff of 0.5 (PS3_Supporting; PMID: 22761713).

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 antibody negative) (PP4_Moderate; PMID: 18382660).

PS4

This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold ( PMID: 18382660, internal lab contributors).

Curation History

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