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.288-1G>C

CA367397326

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 92c13879-49c6-4c6c-a2d5-5e798fbec422

HGVS expressions

NM_001354803.2:c.288-1G>C

NC_000007.14:g.44145281C>G

CM000669.2:g.44145281C>G

NC_000007.13:g.44184880C>G

CM000669.1:g.44184880C>G

NC_000007.12:g.44151405C>G

NG_008847.1:g.49143G>C

NG_008847.2:g.57890G>C

ENST00000395796.8:c.*1252-1G>C

ENST00000616242.5:c.*374-1G>C

ENST00000683378.1:n.480-1G>C

ENST00000336642.9:c.288-1G>C

ENST00000345378.7:c.1257-1G>C

ENST00000403799.8:c.1254-1G>C

ENST00000671824.1:c.1317-1G>C

ENST00000672743.1:n.266-1G>C

ENST00000673284.1:c.1254-1G>C

ENST00000336642.8:n.306-1G>C

ENST00000345378.6:c.1257-1G>C

ENST00000395796.7:c.1251-1G>C

ENST00000403799.7:c.1254-1G>C

ENST00000437084.1:c.1203-1G>C

ENST00000459642.1:n.634-1G>C

ENST00000616242.4:n.1251-1G>C

NM_000162.3:c.1254-1G>C

NM_033507.1:c.1257-1G>C

NM_033508.1:c.1251-1G>C

NM_000162.4:c.1254-1G>C

NM_001354800.1:c.1254-1G>C

NM_001354801.1:c.243-1G>C

NM_001354802.1:c.114-1G>C

NM_001354803.1:c.288-1G>C

NM_033507.2:c.1257-1G>C

NM_033508.2:c.1251-1G>C

NM_000162.5:c.1254-1G>C

NM_033507.3:c.1257-1G>C

NM_033508.3:c.1251-1G>C

Pathogenic

PVS1_Strong PS4 PP1_Moderate PM2_Supporting PP4_Moderate

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.1254-1G>C variant in the glucokinase gene, GCK, is predicted to remove a canonical splice acceptor site in intron 9 of NM_000162.5. While this variant is predicted to cause skipping of exon 10 and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). This variant is also absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 27256595, 32375122, internal lab contributors). Additionally, this variant segregated with diabetes, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors). Lastly, this variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595). In summary, c.1254-1G>C meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_Supporting, PS4, PP1_Moderate, PP4_Moderate.

PVS1_Strong

While this variant is predicted to cause skipping of exon 10 and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1; PMID: 19790256).

PS4

This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 27256595, 32375122, internal lab contributors).

PP1_Moderate

This variant segregated with diabetes/hyperglycemia, with 3 informative meioses in 2 families with MODY (PP1_Moderate; internal lab contributors).

PM2_Supporting

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

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID: 27256595).

Approved on: 2023-07-29

Published on: 2023-07-29

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