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.336C>A

CA367397114

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: b73ffb72-dd55-4174-be2f-2f70fd4e971d

HGVS expressions

NM_001354803.2:c.336C>A

NC_000007.14:g.44145232G>T

CM000669.2:g.44145232G>T

NC_000007.13:g.44184831G>T

CM000669.1:g.44184831G>T

NC_000007.12:g.44151356G>T

NG_008847.1:g.49192C>A

NG_008847.2:g.57939C>A

ENST00000395796.8:c.*1300C>A

ENST00000616242.5:c.*422C>A

ENST00000683378.1:n.528C>A

ENST00000336642.9:c.336C>A

ENST00000345378.7:c.1305C>A

ENST00000403799.8:c.1302C>A

ENST00000671824.1:c.1365C>A

ENST00000672743.1:n.314C>A

ENST00000673284.1:c.1302C>A

ENST00000336642.8:n.354C>A

ENST00000345378.6:c.1305C>A

ENST00000395796.7:c.1299C>A

ENST00000403799.7:c.1302C>A

ENST00000437084.1:c.1251C>A

ENST00000459642.1:n.682C>A

ENST00000616242.4:n.1299C>A

NM_000162.3:c.1302C>A

NM_033507.1:c.1305C>A

NM_033508.1:c.1299C>A

NM_000162.4:c.1302C>A

NM_001354800.1:c.1302C>A

NM_001354801.1:c.291C>A

NM_001354802.1:c.162C>A

NM_001354803.1:c.336C>A

NM_033507.2:c.1305C>A

NM_033508.2:c.1299C>A

NM_000162.5:c.1302C>A

NM_033507.3:c.1305C>A

NM_033508.3:c.1299C>A

Pathogenic

PP1_Strong PVS1 PS4_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.1302C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 434 (p.(Cys434Ter)) of NM_000162.5. While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon 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 absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 28726111, PMID 19564454, internal lab contributor). One of these individuals had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies) (PP4_Moderate; PMID 28726111). Additionally, this variant segregated with diabetes with 5 informative meioses in 2 families with MODY (PP1_Strong; PMID:28726111, internal lab contributor). In summary, the c.1302C>A variant 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, PP1_Strong, PP4_moderate, PS4_moderate, PM2_Supporting).

PP1_Strong

This variant segregated with diabetes with 5 informative meioses in 2 families with MODY (PP1_Strong; PMID:28726111, internal lab contributor).

PVS1

While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon 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_Moderate

This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID 28726111, PMID 19564454, internal lab contributor).

PM2_Supporting

Absent in gnomAD v2.1.1 (PM2_Supporting).

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% and negative antibodies ) (PP4_Moderate; PMID 28726111)

Approved on: 2023-06-25

Published on: 2023-06-25

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