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_033508.3:c.107T>C

CA367403544

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 3d99d62c-0311-40e5-a6bc-20262825de81

HGVS expressions

NM_033508.3:c.107T>C

NC_000007.14:g.44153399A>G

CM000669.2:g.44153399A>G

NC_000007.13:g.44192998A>G

CM000669.1:g.44192998A>G

NC_000007.12:g.44159523A>G

NG_008847.1:g.41025T>C

NG_008847.2:g.49772T>C

ENST00000395796.8:c.*108T>C

ENST00000616242.5:c.110T>C

ENST00000682635.1:n.596T>C

ENST00000345378.7:c.113T>C

ENST00000403799.8:c.110T>C

ENST00000671824.1:c.110T>C

ENST00000673284.1:c.110T>C

ENST00000345378.6:c.113T>C

ENST00000395796.7:c.107T>C

ENST00000403799.7:c.110T>C

ENST00000437084.1:c.110T>C

ENST00000476008.1:n.545T>C

ENST00000616242.4:c.107T>C

NM_000162.3:c.110T>C

NM_033507.1:c.113T>C

NM_033508.1:c.107T>C

NM_000162.4:c.110T>C

NM_001354800.1:c.110T>C

NM_033507.2:c.113T>C

NM_033508.2:c.107T>C

NM_000162.5:c.110T>C

NM_033507.3:c.113T>C

Likely Pathogenic

PP4_Moderate PM5_Supporting PM2_Supporting PP3 PP2

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.110T>C variant in the glucokinase gene, GCK, causes an amino acid change of methionine to threonine at codon 37 (p.(Met37Thr)) of NM_000162.5. 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 persistent impaired fasting glucose) (PP4_Moderate; PMID 28170077). 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.9559, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.110T>C (p.Met37Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met37Thr (PM5_Supporting). This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDS: 33477506, 28170077, internal lab contributors). This variant segregated with diabetes with one informative meiosis in a family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 28170077). In summary, c.110T>C meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PP4_Moderate, PP2, PP3, PM2_Supporting, PM5_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 persistent impaired fasting glucose) (PP4_Moderate; PMID 28170077).

PM5_Supporting

Another missense variant, c.110T>C (p.Met37Arg), has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Met37Thr (PM5_Supporting).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9559, which is greater than the MDEP VCEP 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).

PS4

This variant was identified in three unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDS: 33477506, 28170077, internal lab contributors).

PP1

This variant segregated with diabetes with one informative meiosis in a family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMIDs: 27236918, 28170077).

Approved on: 2023-12-08

Published on: 2023-12-08

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