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_000162.5(GCK):c.630G>T (p.Met210Ile)

CA213814

36236 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: d17187f9-d65a-4117-af07-cfcb9e907236

HGVS expressions

NM_000162.5:c.630G>T

NM_000162.5(GCK):c.630G>T (p.Met210Ile)

NC_000007.14:g.44149809C>A

CM000669.2:g.44149809C>A

NC_000007.13:g.44189408C>A

CM000669.1:g.44189408C>A

NC_000007.12:g.44155933C>A

NG_008847.1:g.44615G>T

NG_008847.2:g.53362G>T

ENST00000395796.8:c.*628G>T

ENST00000616242.5:c.630G>T

ENST00000682635.1:n.1116G>T

ENST00000345378.7:c.633G>T

ENST00000403799.8:c.630G>T

ENST00000671824.1:c.630G>T

ENST00000673284.1:c.630G>T

ENST00000345378.6:c.633G>T

ENST00000395796.7:c.627G>T

ENST00000403799.7:c.630G>T

ENST00000437084.1:c.579G>T

ENST00000616242.4:c.627G>T

NM_000162.3:c.630G>T

NM_033507.1:c.633G>T

NM_033508.1:c.627G>T

NM_000162.4:c.630G>T

NM_001354800.1:c.630G>T

NM_033507.2:c.633G>T

NM_033508.2:c.627G>T

NM_033507.3:c.633G>T

NM_033508.3:c.627G>T

Pathogenic

PS1 PM5_Strong PP3 PP2 PM2_Supporting

PS4 PP4

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>T 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (ClinVar ID 36236). 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). The nucleotide change c.630G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1). Taken together, the c.630G>T 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, PS1, PP2, PP3, PM2_Supporting.

PS1

The nucleotide change c.630G>A, which causes the same amino acid change, has been classified as pathogenic for monogenic diabetes by the ClinGen MDEP (PS1).

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).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.9399, 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).

PM2_Supporting

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

PS4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP4

This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (ClinVar ID 36236).

Approved on: 2024-01-22

Published on: 2024-01-22

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