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.1145G>A (p.Cys382Tyr)

CA367398751

1256304 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: b17e0692-a2da-4e76-9e2b-b28ed6772784

HGVS expressions

NM_000162.5:c.1145G>A

NM_000162.5(GCK):c.1145G>A (p.Cys382Tyr)

NC_000007.14:g.44145605C>T

CM000669.2:g.44145605C>T

NC_000007.13:g.44185204C>T

CM000669.1:g.44185204C>T

NC_000007.12:g.44151729C>T

NG_008847.1:g.48819G>A

NG_008847.2:g.57566G>A

ENST00000395796.8:c.*1143G>A

ENST00000616242.5:c.*265G>A

ENST00000683378.1:n.371G>A

ENST00000336642.9:c.179G>A

ENST00000345378.7:c.1148G>A

ENST00000403799.8:c.1145G>A

ENST00000671824.1:c.1208G>A

ENST00000672743.1:n.157G>A

ENST00000673284.1:c.1145G>A

ENST00000336642.8:n.197G>A

ENST00000345378.6:c.1148G>A

ENST00000395796.7:c.1142G>A

ENST00000403799.7:c.1145G>A

ENST00000437084.1:c.1094G>A

ENST00000459642.1:n.525G>A

ENST00000616242.4:n.1142G>A

NM_000162.3:c.1145G>A

NM_033507.1:c.1148G>A

NM_033508.1:c.1142G>A

NM_000162.4:c.1145G>A

NM_001354800.1:c.1145G>A

NM_001354801.1:c.134G>A

NM_001354802.1:c.5G>A

NM_001354803.1:c.179G>A

NM_033507.2:c.1148G>A

NM_033508.2:c.1142G>A

NM_033507.3:c.1148G>A

NM_033508.3:c.1142G>A

NM_001354803.2:c.179G>A

Pathogenic

PS4 PP4 PP3 PP2 PP1 PM2_Supporting PM5

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.1145G>A variant in the glucokinase gene, GCK, causes an amino acid change of cysteine to tyrosine at codon 382 (p.(Cys382Tyr)) of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 0.922 which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in the homozygous state in three individuals with neonatal diabetes and negative testing for ABCC8, KCNJ11, and INS (internal lab contributors). This variant segregated with diabetes, with 3 informative meioses in 1 family with MODY (PP1; internal lab contributors). Another missense variant, c.1144T>C p.Cys382Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Cys382Tyr has a greater Grantham distance (PM5). This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Zubkova N.A et al, World J PM. 2017;1(1):40-48, https://doi.org/10.14341/WJPM9298, internal lab contributors). In summary, c.1145G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PP1, PP2, PP3, PM2_Supporting, PM5, PP4, PS4.

PS4

This variant was identified in 7 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; Zubkova N.A et al, World J PM. 2017;1(1):40-48. https://doi.org/10.14341/WJPM9298, internal lab contributors).

PP4

This variant was identified in the homozygous state in three individuals with neonatal diabetes and negative testing for ABCC8, KCNJ11, and INS (internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.922 which is greater than or equal to 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).

PP1

This variant segregated with diabetes, with 3 informative meioses in 1 family with MODY (PP1; internal lab contributors).

PM2_Supporting

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

PM5

Another missense variant, c.1144T>C p.Cys382Arg, has been interpreted as pathogenic by the ClinGen MDEP, and p.Cys382Tyr has a greater Grantham distance (PM5).

Approved on: 2023-07-16

Published on: 2023-07-16

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