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]

Variant: NM_001354803.2:c.290T>C

CA367397309

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: ac307cfc-2ced-4b4d-9325-a80acedffe42

Approved on: 2023-10-10

Published on: 2023-10-10

HGVS expressions

NM_001354803.2:c.290T>C

NC_000007.14:g.44145278A>G

CM000669.2:g.44145278A>G

NC_000007.13:g.44184877A>G

CM000669.1:g.44184877A>G

NC_000007.12:g.44151402A>G

NG_008847.1:g.49146T>C

NG_008847.2:g.57893T>C

ENST00000395796.8:c.*1254T>C

ENST00000616242.5:c.*376T>C

ENST00000683378.1:n.482T>C

ENST00000336642.9:c.290T>C

ENST00000345378.7:c.1259T>C

ENST00000403799.8:c.1256T>C

ENST00000671824.1:c.1319T>C

ENST00000672743.1:n.268T>C

ENST00000673284.1:c.1256T>C

ENST00000336642.8:c.308T>C

ENST00000345378.6:c.1259T>C

ENST00000395796.7:c.1253T>C

ENST00000403799.7:c.1256T>C

ENST00000437084.1:c.1205T>C

ENST00000459642.1:n.636T>C

ENST00000616242.4:c.1253T>C

NM_000162.3:c.1256T>C

NM_033507.1:c.1259T>C

NM_033508.1:c.1253T>C

NM_000162.4:c.1256T>C

NM_001354800.1:c.1256T>C

NM_001354801.1:c.245T>C

NM_001354802.1:c.116T>C

NM_001354803.1:c.290T>C

NM_033507.2:c.1259T>C

NM_033508.2:c.1253T>C

NM_000162.5:c.1256T>C

NM_033507.3:c.1259T>C

NM_033508.3:c.1253T>C

Likely Pathogenic

PM2_Supporting PS3_Moderate PP4_Moderate PP3 PP2

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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c. 1256T>C variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 419 (p.(Phe419Ser)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, 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 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: 22493702). A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters passed the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Phe419Ser has RAI<0.01, which is less than the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 22493702). This variant segregated with disease with two informative meioses in a single family with diabetes, however this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 27236918) (PMID 22493702). In summary, this variant meets the criteria to be classified as likely pathogenic for GCK-MODY. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.2.0, approved 6/7/2023): PP2, PP3, PM2_Supporting, PP4_Moderate, PS3_Moderate.

PM2_Supporting

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

PS3_Moderate

A kinetic analysis of recombinant wild-type (WT) and mutant glucokinase demonstrated that the wild-type kinetic parameters pass the quality control, the wild-type ATP Km is between 0.4-0.65, and the p.Phe419Ser has RAI<0.01, which is less than or equal to the MDEP VCEP threshold of 0.50 (PS3_Moderate; PMID 22493702).

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: 22493702).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9739, which is greater than or equal to the MDEP VCEP threshold of 0.70 (PP3).

PP2

GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2).

PP1

This variant segregated with disease with two informative meioses in a single family with diabetes, however this does not meet the thresholds for PP1 set by the ClinGen MDEP VCEP (PMID: 22493702).

Curation History

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