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+1G>A

CA367399681

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 72b8fac7-0135-48cb-be40-e9f09ed1f4b4

Approved on: 2023-11-24

Published on: 2023-11-24

HGVS expressions

NM_033508.3:c.1016+1G>A

NC_000007.14:g.44146462C>T

CM000669.2:g.44146462C>T

NC_000007.13:g.44186061C>T

CM000669.1:g.44186061C>T

NC_000007.12:g.44152586C>T

NG_008847.1:g.47962G>A

NG_008847.2:g.56709G>A

ENST00000395796.8:c.*1017+1G>A

ENST00000616242.5:c.*139+1G>A

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

ENST00000345378.7:c.1022+1G>A

ENST00000403799.8:c.1019+1G>A

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

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

ENST00000345378.6:c.1022+1G>A

ENST00000395796.7:c.1016+1G>A

ENST00000403799.7:c.1019+1G>A

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

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

ENST00000616242.4:c.1016+1G>A

NM_000162.3:c.1019+1G>A

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

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

NM_000162.4:c.1019+1G>A

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

NM_001354801.1:c.8+157G>A

NM_033507.2:c.1022+1G>A

NM_033508.2:c.1016+1G>A

NM_000162.5:c.1019+1G>A

NM_033507.3:c.1022+1G>A

Pathogenic

PVS1 PS4 PM2_Supporting PP4_Moderate

PS1

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.1019+1G>A variant in the glucokinase gene, GCK, is predicted to remove a canonical splice donor site in intron 8 of NM_000162.5. This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256). The nucleotide change c.1019+1G>A was identified in 9 unrelated individuals with hyperglycemia (PS4; PMIDs: 15928245, 28726111, 32533152, 28012402, 36257325, internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Additionally, 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 and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors). The c.1019+1G>T variant at the same canonical nucleotide and has a similar predicted impact by Splice AI (.96 and .96), but PS1_Supporting cannot be applied because the c.1019+1G>T variant is only likely pathogenic before incorporating information about the G>A variant. In summary, c.1019+1G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PVS1, PS4, PM2_Supporting, PP4_Moderate.

PVS1

This variant is predicted to cause skipping of biologically-relevant exon 9 of 10, resulting in a frameshift, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 19790256).

PS4

The nucleotide change c.1019+1G>A was identified in 9 unrelated individuals with hyperglycemia (PS4; PMIDs: 15928245, 28726111, 32533152, 28012402, 36257325, internal lab contributors).

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 negative antibodies and 3 generation family history of diabetes/hyperglycemia) (PP4_Moderate; internal lab contributors).

PS1

The c.1019+1G>T variant at the same canonical nucleotide and has a similar predicted impact by Splice AI (.96 and .96), but PS1_Supporting cannot be applied because the c.1019+1G>T variant is only likely pathogenic before incorporating information about the G>A variant.

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