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_001354803.2:c.432A>G

CA367396716

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 4af7b7e3-ee4b-420c-88ad-d85afd2036fd

Approved on: 2023-08-10

Published on: 2023-08-10

HGVS expressions

NM_001354803.2:c.432A>G

NC_000007.14:g.44145136T>C

CM000669.2:g.44145136T>C

NC_000007.13:g.44184735T>C

CM000669.1:g.44184735T>C

NC_000007.12:g.44151260T>C

NG_008847.1:g.49288A>G

NG_008847.2:g.58035A>G

ENST00000395796.8:c.*1396A>G

ENST00000616242.5:c.*518A>G

ENST00000683378.1:n.624A>G

ENST00000336642.9:c.432A>G

ENST00000345378.7:c.1401A>G

ENST00000403799.8:c.1398A>G

ENST00000671824.1:c.1461A>G

ENST00000672743.1:n.381+29A>G

ENST00000673284.1:c.1369+29A>G

ENST00000336642.8:n.450A>G

ENST00000345378.6:c.1401A>G

ENST00000395796.7:c.1395A>G

ENST00000403799.7:c.1398A>G

ENST00000437084.1:c.1347A>G

ENST00000459642.1:n.778A>G

ENST00000616242.4:n.1395A>G

NM_000162.3:c.1398A>G

NM_033507.1:c.1401A>G

NM_033508.1:c.1395A>G

NM_000162.4:c.1398A>G

NM_001354800.1:c.1369+29A>G

NM_001354801.1:c.387A>G

NM_001354802.1:c.229+29A>G

NM_001354803.1:c.432A>G

NM_033507.2:c.1401A>G

NM_033508.2:c.1395A>G

NM_000162.5:c.1398A>G

NM_033507.3:c.1401A>G

NM_033508.3:c.1395A>G

Likely Pathogenic

PM2_Supporting PVS1

PS4 PP4

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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1398A>G variant in the glucokinase gene, GCK, causes an amino acid change at the stop codon of the final exon (10/10), resulting in the addition of 144 amino acids at the end of the protein (p.(Ter466ArgextTer144)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with a clinical history consistent with GCK-hyperglycemia, but there was insufficient clinical data to evaluate for PP4 (internal lab contributors). Taken together, this evidence supports the classification of this variant as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP: PVS1, PM2_Supporting. (Specification version 1.2.0, approved 6/7/23)

PM2_Supporting

Absent in gnomAD

PVS1

This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256).

PS4

Seen in one individual (internal lab contributors)

PP4

This variant was identified in an individual with a clinical history consistent with GCK-hyperglycemia, but there was insufficient clinical data to evaluate for PP4 (internal lab contributors).

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