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.288-2A>G

CA367397333

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 600abe03-4e65-4e1f-930e-124f8400c5d3

Approved on: 2023-11-03

Published on: 2023-11-03

HGVS expressions

NM_001354803.2:c.288-2A>G

NC_000007.14:g.44145282T>C

CM000669.2:g.44145282T>C

NC_000007.13:g.44184881T>C

CM000669.1:g.44184881T>C

NC_000007.12:g.44151406T>C

NG_008847.1:g.49142A>G

NG_008847.2:g.57889A>G

ENST00000395796.8:c.*1252-2A>G

ENST00000616242.5:c.*374-2A>G

ENST00000683378.1:n.480-2A>G

ENST00000336642.9:c.288-2A>G

ENST00000345378.7:c.1257-2A>G

ENST00000403799.8:c.1254-2A>G

ENST00000671824.1:c.1317-2A>G

ENST00000672743.1:n.266-2A>G

ENST00000673284.1:c.1254-2A>G

ENST00000336642.8:c.306-2A>G

ENST00000345378.6:c.1257-2A>G

ENST00000395796.7:c.1251-2A>G

ENST00000403799.7:c.1254-2A>G

ENST00000437084.1:c.1203-2A>G

ENST00000459642.1:n.634-2A>G

ENST00000616242.4:c.1251-2A>G

NM_000162.3:c.1254-2A>G

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

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

NM_000162.4:c.1254-2A>G

NM_001354800.1:c.1254-2A>G

NM_001354801.1:c.243-2A>G

NM_001354802.1:c.114-2A>G

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

NM_033507.2:c.1257-2A>G

NM_033508.2:c.1251-2A>G

NM_000162.5:c.1254-2A>G

NM_033507.3:c.1257-2A>G

NM_033508.3:c.1251-2A>G

Pathogenic

PVS1 PM2_Supporting PP4_Moderate

PS4 PP1

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.1254-2A>G 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 biologically-relevant exon 10 of 10 and to escape nonsense-mediated decay, it results in the loss of 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 an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, persistent FBG and HbA1c in this range, and a strong family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). In summary, c.1254-2A>G meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting, PP4_Moderate.

PVS1

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

PM2_Supporting

absent in gnomAD

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, persistent FBG and HbA1c in this range, and a strong family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors).

PS4

2 cases in Paris database

PP1

2 meioses in 1 family

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