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>A

CA367403546

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 320234d9-2979-43c1-b1c8-d08308061d60

HGVS expressions

NM_033508.3:c.107T>A

NC_000007.14:g.44153399A>T

CM000669.2:g.44153399A>T

NC_000007.13:g.44192998A>T

CM000669.1:g.44192998A>T

NC_000007.12:g.44159523A>T

NG_008847.1:g.41025T>A

NG_008847.2:g.49772T>A

ENST00000395796.8:c.*108T>A

ENST00000616242.5:c.110T>A

ENST00000682635.1:n.596T>A

ENST00000345378.7:c.113T>A

ENST00000403799.8:c.110T>A

ENST00000671824.1:c.110T>A

ENST00000673284.1:c.110T>A

ENST00000345378.6:c.113T>A

ENST00000395796.7:c.107T>A

ENST00000403799.7:c.110T>A

ENST00000437084.1:c.110T>A

ENST00000476008.1:n.545T>A

ENST00000616242.4:c.107T>A

NM_000162.3:c.110T>A

NM_033507.1:c.113T>A

NM_033508.1:c.107T>A

NM_000162.4:c.110T>A

NM_001354800.1:c.110T>A

NM_033507.2:c.113T>A

NM_033508.2:c.107T>A

NM_000162.5:c.110T>A

NM_033507.3:c.113T>A

Uncertain Significance

PM5 PM2_Supporting PP3 PP2

PP4

Evidence Links 0

Expert Panel

Monogenic Diabetes VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.110T>A variant in the glucokinase gene, GCK, causes an amino acid change of methionine to lysine at codon 37 (p.(Met37Lys)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.9549, 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 phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). Another missense variant, c.110T>G p.Met37Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met37Lys has a greater Grantham distance (PM5). In summary, c.110T>A meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PM5, PP2, PP3, PM2_Supporting.

PM5

Another missense variant, c.110T>G p.Met37Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Met37Lys has a greater Grantham distance (PM5).

PM2_Supporting

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

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9549, 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).

PP4

This variant was identified in an individual with a phenotype suggestive of GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors).

Approved on: 2024-02-02

Published on: 2024-02-02

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