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]

Link to SEPIO compliant JSON-LD document

Variant: NM_033508.3:c.556G>C

CA367401572

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 94f9732a-d797-421b-976c-26a14bdf4973

Approved on: 2024-06-09

Published on: 2024-06-09

HGVS expressions

NM_033508.3:c.556G>C

NC_000007.14:g.44149989C>G

CM000669.2:g.44149989C>G

NC_000007.13:g.44189588C>G

CM000669.1:g.44189588C>G

NC_000007.12:g.44156113C>G

NG_008847.1:g.44435G>C

NG_008847.2:g.53182G>C

ENST00000395796.8:c.*557G>C

ENST00000616242.5:c.559G>C

ENST00000682635.1:n.1045G>C

ENST00000345378.7:c.562G>C

ENST00000403799.8:c.559G>C

ENST00000671824.1:c.559G>C

ENST00000673284.1:c.559G>C

ENST00000345378.6:c.562G>C

ENST00000395796.7:c.556G>C

ENST00000403799.7:c.559G>C

ENST00000437084.1:c.508G>C

ENST00000616242.4:c.556G>C

NM_000162.3:c.559G>C

NM_033507.1:c.562G>C

NM_033508.1:c.556G>C

NM_000162.4:c.559G>C

NM_001354800.1:c.559G>C

NM_033507.2:c.562G>C

NM_033508.2:c.556G>C

NM_000162.5:c.559G>C

NM_033507.3:c.562G>C

Likely Pathogenic

PM2_Supporting PP3 PP2 PP4_Moderate PM5_Supporting

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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.559G>C variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to histidine at codon 187 (p.(Asp187His)) 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 0.85, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (persistent FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate; internal lab contributor). Another missense variant, c.559G>T p.Asp187Tyr, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.559G>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Suppporting, PM5_Supporting.

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.85, 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 (persistent FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4_Moderate; internal lab contributor).

PM5_Supporting

Another missense variant, c.559G>T p.Asp187Tyr, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PM1

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

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