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_000162.5(GCK):c.449T>A (p.Phe150Tyr)

CA231135

129142 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 8f461c2d-5648-4776-a76a-bec2564f0ba7

Approved on: 2024-01-06

Published on: 2024-01-06

HGVS expressions

NM_000162.5:c.449T>A

NM_000162.5(GCK):c.449T>A (p.Phe150Tyr)

NC_000007.14:g.44150990A>T

CM000669.2:g.44150990A>T

NC_000007.13:g.44190589A>T

CM000669.1:g.44190589A>T

NC_000007.12:g.44157114A>T

NG_008847.1:g.43434T>A

NG_008847.2:g.52181T>A

ENST00000395796.8:c.*447T>A

ENST00000616242.5:c.449T>A

ENST00000682635.1:n.935T>A

ENST00000345378.7:c.452T>A

ENST00000403799.8:c.449T>A

ENST00000671824.1:c.449T>A

ENST00000673284.1:c.449T>A

ENST00000345378.6:c.452T>A

ENST00000395796.7:c.446T>A

ENST00000403799.7:c.449T>A

ENST00000437084.1:c.398T>A

ENST00000616242.4:c.446T>A

NM_000162.3:c.449T>A

NM_033507.1:c.452T>A

NM_033508.1:c.446T>A

NM_000162.4:c.449T>A

NM_001354800.1:c.449T>A

NM_033507.2:c.452T>A

NM_033508.2:c.446T>A

NM_033507.3:c.452T>A

NM_033508.3:c.446T>A

Pathogenic

PP4_Moderate PP1_Moderate PM2_Supporting PS3_Moderate PS4 PP3 PP2

PM1

Evidence Links 1

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.449T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 150 (p.(Phe150Tyr)) 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 0.962, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 25306193, 19564454, 32086287, 30663027, 28726111, 22761713, internal lab contributors). One of these individuals had 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; PMID: 28726111). This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.014, which is below the MDEP cutoff (<0.5) (PS3_Moderate, PMID: 22761713). In summary, c.449T>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): PS4, PP1_Moderate, PP4_Moderate, PS3_Moderate, PP2, PP3, 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) (PP4_Moderate; PMID: 28726111).

PP1_Moderate

This variant segregated with hyperglycemia, with 3 informative meioses in 2 families (PP1_Moderate; internal lab contributors).

PM2_Supporting

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

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.014, which is below the MDEP cutoff (<0.5) (PMID: 22761713).

QC parameters met; RAI = 0.014 +/- 0.003 PubMed:22761713

PS4

This variant was identified in 10 unrelated individuals with hyperglycemia (PS4; PMIDs: 25306193, 19564454, 32086287, 30663027, 28726111, 22761713, internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.962, 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).

PM1

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

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