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_033508.3:c.447C>A

CA367401942

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 855d90d4-f026-4d0c-914b-3a4c35485467

Approved on: 2024-03-22

Published on: 2024-03-22

HGVS expressions

NM_033508.3:c.447C>A

NC_000007.14:g.44150989G>T

CM000669.2:g.44150989G>T

NC_000007.13:g.44190588G>T

CM000669.1:g.44190588G>T

NC_000007.12:g.44157113G>T

NG_008847.1:g.43435C>A

NG_008847.2:g.52182C>A

ENST00000395796.8:c.*448C>A

ENST00000616242.5:c.450C>A

ENST00000682635.1:n.936C>A

ENST00000345378.7:c.453C>A

ENST00000403799.8:c.450C>A

ENST00000671824.1:c.450C>A

ENST00000673284.1:c.450C>A

ENST00000345378.6:c.453C>A

ENST00000395796.7:c.447C>A

ENST00000403799.7:c.450C>A

ENST00000437084.1:c.399C>A

ENST00000616242.4:c.447C>A

NM_000162.3:c.450C>A

NM_033507.1:c.453C>A

NM_033508.1:c.447C>A

NM_000162.4:c.450C>A

NM_001354800.1:c.450C>A

NM_033507.2:c.453C>A

NM_033508.2:c.447C>A

NM_000162.5:c.450C>A

NM_033507.3:c.453C>A

Likely Pathogenic

PS3_Moderate PM2_Supporting PP3 PP2 PM5

PS4 PP4

Evidence Links 1

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.450C>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to leucine at codon 150 (p.(Phe150Leu)) 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 0.954, 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 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 16602010, 20337973, 24918535). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.13, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 28842611). Another missense variant, c.449T>A p.Phe150Tyr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Leu has an equal Grantham distance (PM5). In summary, c.450C>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): PM5, PS3_Moderate, PP2, PP3, 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 0.13, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 28842611).

WT parameters met: Kcat = 43.8, S0.5 (ATP 5mM) = 8.82, Hill number = 1.72, ATP Km = 0.47 (at 50 mM glucose), RAI = 0.13 calculated by Matschinsky 2009 method (post Matschinsky 2004) PubMed:28842611

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Absent from gnomAD 4.0.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.954, 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

Another missense variant, c.449T>A p.Phe150Tyr, has been interpreted as pathogenic by the ClinGen MDEP, and p.Phe150Leu has an equal Grantham distance (PM5).

PS4

This variant was identified in 3 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 16602010, 20337973, 24918535)

PP4

This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMIDs: 16602010, 20337973, 24918535).

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