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.1016+5G>A

CA913189165

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: f7ebf5c8-b2d8-43ea-86c4-d3f16ef03738

Approved on: 2023-11-24

Published on: 2023-11-24

HGVS expressions

NM_033508.3:c.1016+5G>A

NC_000007.14:g.44146458C>T

CM000669.2:g.44146458C>T

NC_000007.13:g.44186057C>T

CM000669.1:g.44186057C>T

NC_000007.12:g.44152582C>T

NG_008847.1:g.47966G>A

NG_008847.2:g.56713G>A

ENST00000395796.8:c.*1017+5G>A

ENST00000616242.5:c.*139+5G>A

ENST00000683378.1:n.245+5G>A

ENST00000345378.7:c.1022+5G>A

ENST00000403799.8:c.1019+5G>A

ENST00000671824.1:c.1082+5G>A

ENST00000673284.1:c.1019+5G>A

ENST00000345378.6:c.1022+5G>A

ENST00000395796.7:c.1016+5G>A

ENST00000403799.7:c.1019+5G>A

ENST00000437084.1:c.968+5G>A

ENST00000473353.1:n.317+5G>A

ENST00000616242.4:c.1016+5G>A

NM_000162.3:c.1019+5G>A

NM_033507.1:c.1022+5G>A

NM_033508.1:c.1016+5G>A

NM_000162.4:c.1019+5G>A

NM_001354800.1:c.1019+5G>A

NM_001354801.1:c.8+161G>A

NM_033507.2:c.1022+5G>A

NM_033508.2:c.1016+5G>A

NM_000162.5:c.1019+5G>A

NM_033507.3:c.1022+5G>A

Likely Pathogenic

PP1_Strong PP3 PM2_Supporting PP4_Moderate

PS4

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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1019+5G>A variant in the glucokinase gene, GCK, is a single nucleotide variant within intron 8 of NM_000162.5. This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, this variant segregated with hyperglycemia, with four informative meioses in two families (PP1_Strong; PMIDs: 19564454, 31604004). The computational splicing predictor SpliceAI gives a score of 0.63 for donor gain and 0.50 for donor loss, predicting that the variant disrupts the donor site of intron 8 of GCK (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 antibody negative) (PP4_Moderate; PMID: 31604004). This variant was identified in 2 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMIDs: 19564454, 31604004). In summary, c.1019+5G>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): PM2_Supporting, PP1_Strong, PP3, PP4_Moderate.

PP1_Strong

This variant segregated with hyperglycemia, with four informative meioses in two families (PP1_Strong; PMIDs: 19564454, 31604004).

PP3

The computational splicing predictor SpliceAI gives a score of 0.63 for donor gain and 0.50 for donor loss, predicting that the variant disrupts the donor site of intron 8 of GCK (PP3).

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_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% and antibody negative) (PP4_Moderate; PMID: 31604004).

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 (PMIDs: 19564454, 31604004).

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