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_033508.3:c.627G>A

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA367401296

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 25ef58a4-42b3-4c2a-b7b3-309273022646

Approved on: 2024-01-22

Published on: 2024-01-22

HGVS expressions

NM_033508.3:c.627G>A

NC_000007.14:g.44149809C>T

CM000669.2:g.44149809C>T

NC_000007.13:g.44189408C>T

CM000669.1:g.44189408C>T

NC_000007.12:g.44155933C>T

NG_008847.1:g.44615G>A

NG_008847.2:g.53362G>A

ENST00000395796.8:c.*628G>A

ENST00000616242.5:c.630G>A

ENST00000682635.1:n.1116G>A

ENST00000345378.7:c.633G>A

ENST00000403799.8:c.630G>A

ENST00000671824.1:c.630G>A

ENST00000673284.1:c.630G>A

ENST00000345378.6:c.633G>A

ENST00000395796.7:c.627G>A

ENST00000403799.7:c.630G>A

ENST00000437084.1:c.579G>A

ENST00000616242.4:c.627G>A

NM_000162.3:c.630G>A

NM_033507.1:c.633G>A

NM_033508.1:c.627G>A

NM_000162.4:c.630G>A

NM_001354800.1:c.630G>A

NM_033507.2:c.633G>A

NM_033508.2:c.627G>A

NM_000162.5:c.630G>A

NM_033507.3:c.633G>A

Pathogenic

PP3 PP2 PP4_Moderate PP1_Moderate PS4_Moderate PM2_Supporting PM5_Strong

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.630G>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to isoleucine at codon 210 (p.(Met210Ile)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate, internal lab contributors). Two of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and/or persistent fasting hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong). In summary, c.630G>A 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): PM5_Strong, PP1_Moderate, PP4_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP 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).

PP4_Moderate

This variant was identified in 2 unrelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies and/or persistent fasting hyperglycemia) (PP4_Moderate; internal lab contributors).

PP1_Moderate

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

PS4_Moderate

This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate, internal lab contributors).

PM2_Supporting

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

PM5_Strong

Two other missense variants, c.629T>A (p.Met210Lys) and c.629T>C (p.Met210Thr), have been classified as pathogenic by the ClinGen MDEP (PM5_Strong).

Curation History

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