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]

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Variant: NM_033508.3:c.446_448del

CA2580612107

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 9414f879-23b1-4385-b942-ad1d27bcf56b

Approved on: 2024-02-23

Published on: 2024-02-23

HGVS expressions

NM_033508.3:c.446_448del

NC_000007.14:g.44150990_44150992del

CM000669.2:g.44150990_44150992del

NC_000007.13:g.44190589_44190591del

CM000669.1:g.44190589_44190591del

NC_000007.12:g.44157114_44157116del

NG_008847.1:g.43434_43436del

NG_008847.2:g.52181_52183del

ENST00000395796.8:c.*447_*449del

ENST00000616242.5:c.449_451del

ENST00000682635.1:n.935_937del

ENST00000345378.7:c.452_454del

ENST00000403799.8:c.449_451del

ENST00000671824.1:c.449_451del

ENST00000673284.1:c.449_451del

ENST00000345378.6:c.452_454del

ENST00000395796.7:c.446_448del

ENST00000403799.7:c.449_451del

ENST00000437084.1:c.398_400del

ENST00000616242.4:c.446_448del

NM_000162.3:c.449_451del

NM_033507.1:c.452_454del

NM_033508.1:c.446_448del

NM_000162.4:c.449_451del

NM_001354800.1:c.449_451del

NM_033507.2:c.452_454del

NM_033508.2:c.446_448del

NM_000162.5:c.449_451del

NM_033507.3:c.452_454del

Pathogenic

PM2_Supporting PP1_Moderate PP4_Moderate PM4_Supporting 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.449_451del variant in the glucokinase gene, GCK, is a one-base pair deletion resulting in the in-frame deletion of phenylalanine codon 150 (p.Phe150del) within exon 4 of NM_000162.5. The c.449_451del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a non-repeat region (PM4_Supporting). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMID: 19564454, 31576961, internal lab contributors). 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 antibody) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia, with 3 informative meioses in two families (PP1_Moderate, internal lab contributors). In summary, c.449_451del 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): PM2_Supporting, PM4_Supporting, PP4_Moderate, PP1_Moderate, PS4.

PM2_Supporting

This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Absent from gnomAD 4.0.

PP1_Moderate

This variant segregated with hyperglycemia, with 3 informative meioses in two families (PP1_Moderate, internal lab contributors).

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 antibody) (PP4_Moderate; internal lab contributors).

PM4_Supporting

The c.449_451del variant is predicted to change the length of the protein due to an in-frame deletion of a single amino acid in a non-repeat region (PM4_Supporting).

PS4

This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMID: 19564454, 31576961, internal lab contributors).

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