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.1087G>A (p.Asp363Asn)

CA16618466

418228 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 91bdc867-15f1-4bc5-842f-c7d56ac49e83

HGVS expressions

NM_000162.5:c.1087G>A

NM_000162.5(GCK):c.1087G>A (p.Asp363Asn)

NC_000007.14:g.44145663C>T

CM000669.2:g.44145663C>T

NC_000007.13:g.44185262C>T

CM000669.1:g.44185262C>T

NC_000007.12:g.44151787C>T

NG_008847.1:g.48761G>A

NG_008847.2:g.57508G>A

ENST00000395796.8:c.*1085G>A

ENST00000616242.5:c.*207G>A

ENST00000683378.1:n.313G>A

ENST00000336642.9:c.121G>A

ENST00000345378.7:c.1090G>A

ENST00000403799.8:c.1087G>A

ENST00000671824.1:c.1150G>A

ENST00000672743.1:n.99G>A

ENST00000673284.1:c.1087G>A

ENST00000336642.8:c.139G>A

ENST00000345378.6:c.1090G>A

ENST00000395796.7:c.1084G>A

ENST00000403799.7:c.1087G>A

ENST00000437084.1:c.1036G>A

ENST00000459642.1:n.467G>A

ENST00000473353.1:n.385G>A

ENST00000616242.4:c.1084G>A

NM_000162.3:c.1087G>A

NM_033507.1:c.1090G>A

NM_033508.1:c.1084G>A

NM_000162.4:c.1087G>A

NM_001354800.1:c.1087G>A

NM_001354801.1:c.76G>A

NM_001354802.1:c.-54G>A

NM_001354803.1:c.121G>A

NM_033507.2:c.1090G>A

NM_033508.2:c.1084G>A

NM_033507.3:c.1090G>A

NM_033508.3:c.1084G>A

NM_001354803.2:c.121G>A

Likely Pathogenic

PP4_Moderate PM2_Supporting PM5_Supporting PP3 PP2

PM1 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 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1087G>A variant in the glucokinase gene, GCK, causes an amino acid change of aspartic acid to asparagine at codon 363 (p.(Asp363Asn)) of NM_000162.5. This variant was identified in at least 1 individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:19790256, 36257325, internal lab contributor). The individual had a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative antibodies, and three-generation, dominant family history of diabetes (in a family not used for PP1)) (PP4_Moderate; internal lab contributor).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 0.869, which is greater than the MDEP VCEP threshold of 0.70 (PP3). Another missense variant, c.1088A>G (p.Asp363Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1087G>A 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, PM2_Suporting, PP2, PP3, PM5_Supporting.

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%, negative antibodies, and a three-generation, dominant family history of diabetes/hyperglycemia (in a family not used for PP1) (PP4_Moderate, internal lab contributor).

PM2_Supporting

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

PM5_Supporting

Another missense variant, c.1088A>G (p.Asp363Gly), has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.869, which is greater than the MDEP VCEP threshold of 0.70.

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.

PM1

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

PS4

This variant was identified in at least 1 individual with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs:19790256, 36257325, internal lab contributor).

PP1

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

Approved on: 2024-01-22

Published on: 2024-01-22

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