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.660C>A (p.Cys220Ter)

CA367401189

1172896 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: a0440cfd-bea7-4669-9015-029cdffa3640

HGVS expressions

NM_000162.5:c.660C>A

NM_000162.5(GCK):c.660C>A (p.Cys220Ter)

NC_000007.14:g.44149779G>T

CM000669.2:g.44149779G>T

NC_000007.13:g.44189378G>T

CM000669.1:g.44189378G>T

NC_000007.12:g.44155903G>T

NG_008847.1:g.44645C>A

NG_008847.2:g.53392C>A

ENST00000395796.8:c.*658C>A

ENST00000616242.5:c.660C>A

ENST00000682635.1:n.1146C>A

ENST00000345378.7:c.663C>A

ENST00000403799.8:c.660C>A

ENST00000671824.1:c.660C>A

ENST00000673284.1:c.660C>A

ENST00000345378.6:c.663C>A

ENST00000395796.7:c.657C>A

ENST00000403799.7:c.660C>A

ENST00000437084.1:c.609C>A

ENST00000616242.4:c.657C>A

NM_000162.3:c.660C>A

NM_033507.1:c.663C>A

NM_033508.1:c.657C>A

NM_000162.4:c.660C>A

NM_001354800.1:c.660C>A

NM_033507.2:c.663C>A

NM_033508.2:c.657C>A

NM_033507.3:c.663C>A

NM_033508.3:c.657C>A

Pathogenic

PS4 PP4 PM2_Supporting PVS1 PP1_Strong

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 1.3.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.660C>A variant in the glucokinase gene, GCK, results in a premature termination at codon 220 (p.(Cys220Ter)) of NM_000162.5. This variant, located in exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 9790256). This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in multiple families (PP1_Strong; internal lab contributors). This variant was identified in at least 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 21348868, 3347750, 31638168, 20337973, 12627330, 16602010, internal lab contributors. This variant was identified in at least 2 individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, c.660C>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0 approved 8/11/2023): PVS1, PP1_Strong, PS4, PP4, PM2_Supporting.

PS4

This variant was identified in at least 11 unrelated individuals with hyperglycemia (PS4; PMIDs: 21348868, 3347750, 31638168, 20337973, 12627330, 16602010, internal lab contributors.

PP4

This variant was identified in at least 2 individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; internal lab contributors).

PM2_Supporting

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

PVS1

This variant, located in exon 6 of 10, is predicted to lead to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 9790256).

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with 5 informative meioses in multiple families (PP1_Strong; internal lab contributors).

PM1

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

Approved on: 2023-10-13

Published on: 2023-10-13

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