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]

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Variant: NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)

CA367399180

804832 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7a4344bd-0fd2-41f0-af5c-d0c79a7cd210

HGVS expressions

NM_000162.5:c.1064T>C

NM_000162.5(GCK):c.1064T>C (p.Leu355Pro)

NC_000007.14:g.44145686A>G

CM000669.2:g.44145686A>G

NC_000007.13:g.44185285A>G

CM000669.1:g.44185285A>G

NC_000007.12:g.44151810A>G

NG_008847.1:g.48738T>C

NG_008847.2:g.57485T>C

ENST00000395796.8:c.*1062T>C

ENST00000616242.5:c.*184T>C

ENST00000683378.1:n.290T>C

ENST00000336642.9:c.98T>C

ENST00000345378.7:c.1067T>C

ENST00000403799.8:c.1064T>C

ENST00000671824.1:c.1127T>C

ENST00000672743.1:n.76T>C

ENST00000673284.1:c.1064T>C

ENST00000336642.8:n.116T>C

ENST00000345378.6:c.1067T>C

ENST00000395796.7:c.1061T>C

ENST00000403799.7:c.1064T>C

ENST00000437084.1:c.1013T>C

ENST00000459642.1:n.444T>C

ENST00000473353.1:n.362T>C

ENST00000616242.4:n.1061T>C

NM_000162.3:c.1064T>C

NM_033507.1:c.1067T>C

NM_033508.1:c.1061T>C

NM_000162.4:c.1064T>C

NM_001354800.1:c.1064T>C

NM_001354801.1:c.53T>C

NM_001354802.1:c.-77T>C

NM_001354803.1:c.98T>C

NM_033507.2:c.1067T>C

NM_033508.2:c.1061T>C

NM_033507.3:c.1067T>C

NM_033508.3:c.1061T>C

NM_001354803.2:c.98T>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.1064T>C variant in the glucokinase gene, GCK, causes an amino acid change of Leucine to Proline at codon 355 (p.(Leu355Pro)) 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 0.9689, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting), and was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, as well as in two individuals in ClinVar whose clinical status was not known DOI:10.1055/s-2004-819152, ClinVar ID 804832, internal lab contributor). However, PS4_Moderate cannot be applied because the number of affected individuals is below the ClinGen MDEP threshold. This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors). In summary, the evidence supports the classification of c.1064T>C as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP4_Moderate, PP2, PP3, PM2_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 0.9689, which is greater than the MDEP 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-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and 3-generation family history of diabetes) (PP4_Moderate; internal lab contributors).

PS4

This variant was identified in two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes, as well as in two individuals in ClinVar whose clinical status was not known; however, PS4_Moderate cannot be applied because the number of affected individuals is below the ClinGen MDEP threshold (DOI: 10.1055/s-2004-819152, ClinVar ID 804832, internal lab contributor).

Approved on: 2023-07-18

Published on: 2023-07-18

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