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_000162.5(GCK):c.1181G>C (p.Arg394Pro)

CA367398581

2169517 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: bb53053f-9f55-45c8-90ae-bd1ac0c7d3af

HGVS expressions

NM_000162.5:c.1181G>C

NM_000162.5(GCK):c.1181G>C (p.Arg394Pro)

NC_000007.14:g.44145569C>G

CM000669.2:g.44145569C>G

NC_000007.13:g.44185168C>G

CM000669.1:g.44185168C>G

NC_000007.12:g.44151693C>G

NG_008847.1:g.48855G>C

NG_008847.2:g.57602G>C

ENST00000395796.8:c.*1179G>C

ENST00000616242.5:c.*301G>C

ENST00000683378.1:n.407G>C

ENST00000336642.9:c.215G>C

ENST00000345378.7:c.1184G>C

ENST00000403799.8:c.1181G>C

ENST00000671824.1:c.1244G>C

ENST00000672743.1:n.193G>C

ENST00000673284.1:c.1181G>C

ENST00000336642.8:n.233G>C

ENST00000345378.6:c.1184G>C

ENST00000395796.7:c.1178G>C

ENST00000403799.7:c.1181G>C

ENST00000437084.1:c.1130G>C

ENST00000459642.1:n.561G>C

ENST00000616242.4:n.1178G>C

NM_000162.3:c.1181G>C

NM_033507.1:c.1184G>C

NM_033508.1:c.1178G>C

NM_000162.4:c.1181G>C

NM_001354800.1:c.1181G>C

NM_001354801.1:c.170G>C

NM_001354802.1:c.41G>C

NM_001354803.1:c.215G>C

NM_033507.2:c.1184G>C

NM_033508.2:c.1178G>C

NM_033507.3:c.1184G>C

NM_033508.3:c.1178G>C

NM_001354803.2:c.215G>C

Uncertain Significance

PM2_Supporting PP3 PP2 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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1181G>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 394 (p.(Arg394Pro)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.851, 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-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6%, and OGTT increment < 3 mmol/L)(PP4_Moderate; internal lab contributors). This variant was identified in two unrelated individuals with a diabetes; however, this number does not meet the MDEP cutoff for PS4_Moderate (internal lab contributors). In summary, this variant meets the criteria to be classified as uncertain significance for GENE-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP: PP2, PP3, PM2_Supporting, PP4_Moderate (specification version 1.2.0, approved 6/7/2023).

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 0.851, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3).

PP2

GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L, HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L)(PP4_Moderate; internal lab contributors).

PS4

This variant was identified in two unrelated individuals with a diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate (internal lab contributors)

Approved on: 2023-07-16

Published on: 2023-07-16

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