Evidence Repository - GenboreeKB

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000162.5(GCK):c.455T>C (p.Phe152Ser)

Curation Version - 1.0
Curation History
JSON LD for Version 1.0

CA367401925

1741488 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: b8a8c2fb-7517-4e9e-a2e5-a4a95d0a14cb

Approved on: 2024-04-18

Published on: 2024-04-18

HGVS expressions

NM_000162.5:c.455T>C

NM_000162.5(GCK):c.455T>C (p.Phe152Ser)

NC_000007.14:g.44150984A>G

CM000669.2:g.44150984A>G

NC_000007.13:g.44190583A>G

CM000669.1:g.44190583A>G

NC_000007.12:g.44157108A>G

NG_008847.1:g.43440T>C

NG_008847.2:g.52187T>C

ENST00000395796.8:c.*453T>C

ENST00000616242.5:c.455T>C

ENST00000682635.1:n.941T>C

ENST00000345378.7:c.458T>C

ENST00000403799.8:c.455T>C

ENST00000671824.1:c.455T>C

ENST00000673284.1:c.455T>C

ENST00000345378.6:c.458T>C

ENST00000395796.7:c.452T>C

ENST00000403799.7:c.455T>C

ENST00000437084.1:c.404T>C

ENST00000616242.4:c.452T>C

NM_000162.3:c.455T>C

NM_033507.1:c.458T>C

NM_033508.1:c.452T>C

NM_000162.4:c.455T>C

NM_001354800.1:c.455T>C

NM_033507.2:c.458T>C

NM_033508.2:c.452T>C

NM_033507.3:c.458T>C

NM_033508.3:c.452T>C

Pathogenic

PM2_Supporting PP2 PP3 PM5 PP1_Strong PP4_Moderate

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.455T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to serine at codon 152 (p.(Phe152Ser)) 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 0.981, 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 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; PMID: 21978167). This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families (PP1_Strong; PMID: 21978167, internal lab contributors]). Another missense variant, c.454T>C p.(Phe152Leu) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Phe152Ser) has an equal or greater Grantham distance (PM5). In summary, c.455T>C meets the criteria to be classified as a variant of 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, PP3, PP2, PM5, PP4_Moderate, PP1_Strong.

PM2_Supporting

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

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).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.981, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PM5

Another missense variant, c.454T>C p.(Phe152Leu) has been interpreted as pathogenic by the ClinGen MDEP, and p.(Phe152Ser) has an equal or greater Grantham distance (PM5).

PP1_Strong

This variant segregated with diabetes/hyperglycemia, with four informative meioses in two families with MODY (PP1_Strong; PMID: 21978167, 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; PMID: 21978167).

Curation History

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