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_001354803.2:c.365G>A

CA367396980

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7629d129-0dab-4076-884b-ad8c178a58e7

HGVS expressions

NM_001354803.2:c.365G>A

NC_000007.14:g.44145203C>T

CM000669.2:g.44145203C>T

NC_000007.13:g.44184802C>T

CM000669.1:g.44184802C>T

NC_000007.12:g.44151327C>T

NG_008847.1:g.49221G>A

NG_008847.2:g.57968G>A

ENST00000395796.8:c.*1329G>A

ENST00000616242.5:c.*451G>A

ENST00000683378.1:n.557G>A

ENST00000336642.9:c.365G>A

ENST00000345378.7:c.1334G>A

ENST00000403799.8:c.1331G>A

ENST00000671824.1:c.1394G>A

ENST00000672743.1:n.343G>A

ENST00000673284.1:c.1331G>A

ENST00000336642.8:c.383G>A

ENST00000345378.6:c.1334G>A

ENST00000395796.7:c.1328G>A

ENST00000403799.7:c.1331G>A

ENST00000437084.1:c.1280G>A

ENST00000459642.1:n.711G>A

ENST00000616242.4:c.1328G>A

NM_000162.3:c.1331G>A

NM_033507.1:c.1334G>A

NM_033508.1:c.1328G>A

NM_000162.4:c.1331G>A

NM_001354800.1:c.1331G>A

NM_001354801.1:c.320G>A

NM_001354802.1:c.191G>A

NM_001354803.1:c.365G>A

NM_033507.2:c.1334G>A

NM_033508.2:c.1328G>A

NM_000162.5:c.1331G>A

NM_033507.3:c.1334G>A

NM_033508.3:c.1328G>A

Uncertain Significance

PM2_Supporting PP3 PP2 PP4_Moderate

PS4 PM1

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.1331G>A variant in the glucokinase gene, GCK, causes an amino acid change of glycine to aspartic acid at codon 444 (p.(Gly444Asp)) 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 0.956, which is greater than the MDEP VCEP threshold of 0.70 (PP3). 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% and negative antibodies) (PP4_Moderate; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 34826540, internal lab contributors). In summary, c.1331G>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): PP2, PP3, PP4_Moderate, PM2_Supporting.

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 0.956, 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_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% and negative antibodies) (PP4; internal lab contributors).

PS4

This variant was identified in two unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 34826540, internal lab contributors).

PM1

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

Approved on: 2023-11-23

Published on: 2023-11-23

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