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.371A>T (p.Asp124Val)

CA367402205

522504 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 180e8e42-c11a-4d3a-938c-f9470b35a42b

Approved on: 2024-03-14

Published on: 2024-03-14

HGVS expressions

NM_000162.5:c.371A>T

NM_000162.5(GCK):c.371A>T (p.Asp124Val)

NC_000007.14:g.44151068T>A

CM000669.2:g.44151068T>A

NC_000007.13:g.44190667T>A

CM000669.1:g.44190667T>A

NC_000007.12:g.44157192T>A

NG_008847.1:g.43356A>T

NG_008847.2:g.52103A>T

ENST00000395796.8:c.*369A>T

ENST00000616242.5:c.371A>T

ENST00000682635.1:n.857A>T

ENST00000345378.7:c.374A>T

ENST00000403799.8:c.371A>T

ENST00000671824.1:c.371A>T

ENST00000673284.1:c.371A>T

ENST00000345378.6:c.374A>T

ENST00000395796.7:c.368A>T

ENST00000403799.7:c.371A>T

ENST00000437084.1:c.364-44A>T

ENST00000616242.4:c.368A>T

NM_000162.3:c.371A>T

NM_033507.1:c.374A>T

NM_033508.1:c.368A>T

NM_000162.4:c.371A>T

NM_001354800.1:c.371A>T

NM_033507.2:c.374A>T

NM_033508.2:c.368A>T

NM_033507.3:c.374A>T

NM_033508.3:c.368A>T

Uncertain Significance

PM5 PM2_Supporting PP3 PP2

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.371A>T variant in the glucokinase gene, GCK, causes an amino acid change of aspartate to valine at codon 124 (p.(Asp124Val)) 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 0.986, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.370G>A, p.(Asp124Asn) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Asp124Val) has a greater Grantham distance (PM5). In summary, c.449T>C meets the criteria to be classified as uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PM5, PP2, PP3, PM2_Supporting.

PM5

Another missense variant, c.370G>A, p.(Asp124Asn) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Asp124Val) has a greater Grantham distance (PM5).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). absent from gnomAD v4.0.0

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.986, 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).

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