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.952G>A (p.Gly318Arg)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA367399913

585929 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 394f1ba1-710d-4b48-8ac4-eeface1f9358

Approved on: 2025-01-16

Published on: 2025-01-29

HGVS expressions

NM_000162.5:c.952G>A

NM_000162.5(GCK):c.952G>A (p.Gly318Arg)

NC_000007.14:g.44146530C>T

CM000669.2:g.44146530C>T

NC_000007.13:g.44186129C>T

CM000669.1:g.44186129C>T

NC_000007.12:g.44152654C>T

NG_008847.1:g.47894G>A

NG_008847.2:g.56641G>A

ENST00000395796.8:c.*950G>A

ENST00000616242.5:c.*72G>A

ENST00000683378.1:n.178G>A

ENST00000345378.7:c.955G>A

ENST00000403799.8:c.952G>A

ENST00000671824.1:c.1015G>A

ENST00000673284.1:c.952G>A

ENST00000345378.6:c.955G>A

ENST00000395796.7:c.949G>A

ENST00000403799.7:c.952G>A

ENST00000437084.1:c.901G>A

ENST00000473353.1:n.250G>A

ENST00000616242.4:c.949G>A

NM_000162.3:c.952G>A

NM_033507.1:c.955G>A

NM_033508.1:c.949G>A

NM_000162.4:c.952G>A

NM_001354800.1:c.952G>A

NM_001354801.1:c.8+89G>A

NM_033507.2:c.955G>A

NM_033508.2:c.949G>A

NM_033507.3:c.955G>A

NM_033508.3:c.949G>A

Pathogenic

PP1_Strong PS4 PP4_Moderate PP3 PP2 PM2_Supporting

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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.952G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to arginine at codon 318 (p.(Gly318Arg)) 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 absent from gnomAD v2.1.1 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.855, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Furthemore, this variant was identified in over 40 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 28663157, 31416898, 31595705, 32375122, 34440516, 34496959, 36257325, 36400171, 37812285, 12627330, 22332836, 26552609, 26641800, 35472491, and 36208343). This variant segregated with hyperglycemia with at least 17 informative meioses in multiple families (PP1_Strong; PMIDs: 31595705, 34440516, 36257325). Additionally, 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 OGTT with minimal increment (<3mmol/L) (PP4_Moderate; PMID: 31416898). In summary, c.952G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/23): PS4, PP1_Strong, PP4_Moderate, PP2, PP3, PM2_Supporting.

PP1_Strong

This variant segregated with hyperglycemia with at least 17 informative meioses in multiple families (PP1_Strong; PMIDs: 31595705, 34440516, 36257325).

PS4

This variant was identified in over 40 unrelated individuals with hyperglycemia (PS4; PMIDs: 20337973, 28663157, 31416898, 31595705, 32375122, 34440516, 34496959, 36257325, 36400171, 37812285, 12627330, 22332836, 26552609, 26641800, 35472491,m and 36208343).

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 OGTT with minimal increment (<3mmol/L) (PP4_Moderate; PMID: 31416898).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.855, 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).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting).

Curation History

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