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.1289T>C (p.Leu430Pro)

CA213749

36194 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 95f4d325-8f63-4245-a559-09e270cc8af9

HGVS expressions

NM_000162.5:c.1289T>C

NM_000162.5(GCK):c.1289T>C (p.Leu430Pro)

NC_000007.14:g.44145245A>G

CM000669.2:g.44145245A>G

NC_000007.13:g.44184844A>G

CM000669.1:g.44184844A>G

NC_000007.12:g.44151369A>G

NG_008847.1:g.49179T>C

NG_008847.2:g.57926T>C

ENST00000395796.8:c.*1287T>C

ENST00000616242.5:c.*409T>C

ENST00000683378.1:n.515T>C

ENST00000336642.9:c.323T>C

ENST00000345378.7:c.1292T>C

ENST00000403799.8:c.1289T>C

ENST00000671824.1:c.1352T>C

ENST00000672743.1:n.301T>C

ENST00000673284.1:c.1289T>C

ENST00000336642.8:c.341T>C

ENST00000345378.6:c.1292T>C

ENST00000395796.7:c.1286T>C

ENST00000403799.7:c.1289T>C

ENST00000437084.1:c.1238T>C

ENST00000459642.1:n.669T>C

ENST00000616242.4:c.1286T>C

NM_000162.3:c.1289T>C

NM_033507.1:c.1292T>C

NM_033508.1:c.1286T>C

NM_000162.4:c.1289T>C

NM_001354800.1:c.1289T>C

NM_001354801.1:c.278T>C

NM_001354802.1:c.149T>C

NM_001354803.1:c.323T>C

NM_033507.2:c.1292T>C

NM_033508.2:c.1286T>C

NM_033507.3:c.1292T>C

NM_033508.3:c.1286T>C

NM_001354803.2:c.323T>C

Uncertain Significance

PP3 PP2 PM2_Supporting

BS1 BP4 PS4 BA1 PP4 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.1289T>C variant in the glucokinase gene, GCK, causes an amino acid change of leucine to proline at codon 430 (p.(Leu430Pro)) 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). 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: 30191644, internal lab contributors). In summary, c.1289T>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): PM2_supporting, PP2, PP3.

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).

PM2_Supporting

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

BS1

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

BP4

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

PS4

Observed once in Johnson 2019 (PMID:30191644) and internal lab contributor with no clinical information.

BA1

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

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: 30191644, internal lab contributors).

PM1

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

Approved on: 2024-04-27

Published on: 2024-04-27

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