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.677T>C (p.Val226Ala)

CA213828

36244 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 06989f1f-d6e7-4ad1-ba67-9eba226362ca

HGVS expressions

NM_000162.5:c.677T>C

NM_000162.5(GCK):c.677T>C (p.Val226Ala)

NC_000007.14:g.44149762A>G

CM000669.2:g.44149762A>G

NC_000007.13:g.44189361A>G

CM000669.1:g.44189361A>G

NC_000007.12:g.44155886A>G

NG_008847.1:g.44662T>C

NG_008847.2:g.53409T>C

ENST00000395796.8:c.*675T>C

ENST00000616242.5:c.677T>C

ENST00000682635.1:n.1163T>C

ENST00000345378.7:c.680T>C

ENST00000403799.8:c.677T>C

ENST00000671824.1:c.677T>C

ENST00000673284.1:c.677T>C

ENST00000345378.6:c.680T>C

ENST00000395796.7:c.674T>C

ENST00000403799.7:c.677T>C

ENST00000437084.1:c.626T>C

ENST00000616242.4:c.674T>C

NM_000162.3:c.677T>C

NM_033507.1:c.680T>C

NM_033508.1:c.674T>C

NM_000162.4:c.677T>C

NM_001354800.1:c.677T>C

NM_033507.2:c.680T>C

NM_033508.2:c.674T>C

NM_033507.3:c.680T>C

NM_033508.3:c.674T>C

Likely Pathogenic

PM2_Supporting PP3 PP2 PM5_Supporting 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.677T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 226 (p.(Val226Ala)) of NM_000162.5. This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1). 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 0.822, 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.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Ala (PM5_Supporting). In summary, c.677T>C 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): PM1, PP2, PP3, PM2_Supporting, PM5_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 0.822, 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.676G>A p.Val226Met, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Val226Ala (PM5_Supporting).

PM1

This variant resides in an amino acid that directly binds glucose, which is defined as critical for the protein’s function by the ClinGen MDEP (PM1).

Approved on: 2023-10-13

Published on: 2023-10-13

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