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.364C>A (p.Leu122Ile)

CA367402232

435307 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 411e8389-5fc7-42f7-93da-64160c730df4

Approved on: 2024-03-07

Published on: 2024-03-07

HGVS expressions

NM_000162.5:c.364C>A

NM_000162.5(GCK):c.364C>A (p.Leu122Ile)

NC_000007.14:g.44151075G>T

CM000669.2:g.44151075G>T

NC_000007.13:g.44190674G>T

CM000669.1:g.44190674G>T

NC_000007.12:g.44157199G>T

NG_008847.1:g.43349C>A

NG_008847.2:g.52096C>A

ENST00000395796.8:c.*362C>A

ENST00000616242.5:c.364C>A

ENST00000682635.1:n.850C>A

ENST00000345378.7:c.367C>A

ENST00000403799.8:c.364C>A

ENST00000671824.1:c.364C>A

ENST00000673284.1:c.364C>A

ENST00000345378.6:c.367C>A

ENST00000395796.7:c.361C>A

ENST00000403799.7:c.364C>A

ENST00000437084.1:c.364-51C>A

ENST00000616242.4:c.361C>A

NM_000162.3:c.364C>A

NM_033507.1:c.367C>A

NM_033508.1:c.361C>A

NM_000162.4:c.364C>A

NM_001354800.1:c.364C>A

NM_033507.2:c.367C>A

NM_033508.2:c.361C>A

NM_033507.3:c.367C>A

NM_033508.3:c.361C>A

Likely Pathogenic

PP3 PP2 PM5_Supporting PM2 PP4_Moderate

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.364C>A variant in the glucokinase gene, GCK, causes an amino acid change of leucine to isoleucine at codon 122 (p.(Leu122Ile)) 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 0.91, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). 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; internal lab contributors). Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). Taken together, this evidence supports the classification of c.364C>A 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, PM2_Supporting, PM5_Supporting, PP2, PP3.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.91, 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).

PM5_Supporting

Another missense variant, c.364C>T, p.Leu122Phe, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PM2

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). gnomAD v4.0.0 Popmax filtering allele frequency due to one copy in the European non-Finnish subpopulation and no copies in any other subpopulation

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; internal lab contributors).

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