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.1361C>A (p.Ala454Glu)

CA16609264

393447 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 5373061c-5c70-4d02-bd9c-c75b82ee851e

HGVS expressions

NM_000162.5:c.1361C>A

NM_000162.5(GCK):c.1361C>A (p.Ala454Glu)

NC_000007.14:g.44145173G>T

CM000669.2:g.44145173G>T

NC_000007.13:g.44184772G>T

CM000669.1:g.44184772G>T

NC_000007.12:g.44151297G>T

NG_008847.1:g.49251C>A

NG_008847.2:g.57998C>A

ENST00000395796.8:c.*1359C>A

ENST00000616242.5:c.*481C>A

ENST00000683378.1:n.587C>A

ENST00000336642.9:c.395C>A

ENST00000345378.7:c.1364C>A

ENST00000403799.8:c.1361C>A

ENST00000671824.1:c.1424C>A

ENST00000672743.1:n.373C>A

ENST00000673284.1:c.1361C>A

ENST00000336642.8:c.413C>A

ENST00000345378.6:c.1364C>A

ENST00000395796.7:c.1358C>A

ENST00000403799.7:c.1361C>A

ENST00000437084.1:c.1310C>A

ENST00000459642.1:n.741C>A

ENST00000616242.4:c.1358C>A

NM_000162.3:c.1361C>A

NM_033507.1:c.1364C>A

NM_033508.1:c.1358C>A

NM_000162.4:c.1361C>A

NM_001354800.1:c.1361C>A

NM_001354801.1:c.350C>A

NM_001354802.1:c.221C>A

NM_001354803.1:c.395C>A

NM_033507.2:c.1364C>A

NM_033508.2:c.1358C>A

NM_033507.3:c.1364C>A

NM_033508.3:c.1358C>A

NM_001354803.2:c.395C>A

Likely Pathogenic

PM2_Supporting PS3_Moderate PS4_Moderate PP3 PP2

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.1361C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glutamic acid at codon 454 (p.(Ala454Glu)) 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 0.965, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.04, which is below the MDEP cutoff (<0.5) (PMID: 28842611). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 393447, PMIDs: 36257325, 20337973, 16602010, 17204055, internal lab contributors). In summary, c.1361C>A 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): PS3_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.

PM2_Supporting

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

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.04, which is below the MDEP cutoff (<0.5) (PMID: 28842611).

PS4_Moderate

This variant was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 393447, PMIDs: 36257325, 20337973, 16602010, 17204055, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.965, 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).

PM1

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

Approved on: 2024-03-31

Published on: 2024-03-31

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