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.1255T>C (p.Phe419Leu)

CA367397316

447388 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 5630dd6e-3f28-434f-a847-c13cbb24dcb4

HGVS expressions

NM_000162.5:c.1255T>C

NM_000162.5(GCK):c.1255T>C (p.Phe419Leu)

NC_000007.14:g.44145279A>G

CM000669.2:g.44145279A>G

NC_000007.13:g.44184878A>G

CM000669.1:g.44184878A>G

NC_000007.12:g.44151403A>G

NG_008847.1:g.49145T>C

NG_008847.2:g.57892T>C

ENST00000395796.8:c.*1253T>C

ENST00000616242.5:c.*375T>C

ENST00000683378.1:n.481T>C

ENST00000336642.9:c.289T>C

ENST00000345378.7:c.1258T>C

ENST00000403799.8:c.1255T>C

ENST00000671824.1:c.1318T>C

ENST00000672743.1:n.267T>C

ENST00000673284.1:c.1255T>C

ENST00000336642.8:n.307T>C

ENST00000345378.6:c.1258T>C

ENST00000395796.7:c.1252T>C

ENST00000403799.7:c.1255T>C

ENST00000437084.1:c.1204T>C

ENST00000459642.1:n.635T>C

ENST00000616242.4:n.1252T>C

NM_000162.3:c.1255T>C

NM_033507.1:c.1258T>C

NM_033508.1:c.1252T>C

NM_000162.4:c.1255T>C

NM_001354800.1:c.1255T>C

NM_001354801.1:c.244T>C

NM_001354802.1:c.115T>C

NM_001354803.1:c.289T>C

NM_033507.2:c.1258T>C

NM_033508.2:c.1252T>C

NM_033507.3:c.1258T>C

NM_033508.3:c.1252T>C

NM_001354803.2:c.289T>C

Uncertain Significance

PM5_Supporting PP3 PP2 PM2_Supporting

PS4 PP4

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.1255T>C variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to leucine at codon 419 (p.(Phe419Leu)) of NM_000162.5. GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, 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 three unrelated individuals with diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 17204055, 20337973, 16602010, internal lab contributors). One of these individuals had a clinical history consistent with GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMIDs: 17204055, 20337973, 16602010). Another missense variant, c.1256T>C p.Phe419Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP2, PP3, PM2_Supporting, PM5_Supporting.

PM5_Supporting

Another missense variant, c.1256T>C p.Phe419Ser, has been classified as likely pathogenic by the ClinGen MDEP VCEP (PM5_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3).

PP2

GCK is defined by the ClinGen MDEP VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2).

PM2_Supporting

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

PS4

This variant was identified in three unrelated individuals with diabetes, however PS4_Moderate cannot be applied because this number is below the MDEP threshold (PMIDs: 17204055, 20337973, 16602010, internal lab contributors).

PP4

This variant was identified in an individual with a clinical history consistent with GCK-hyperglycemia; however, PP4 is unable to be evaluated due to insufficient clinical information (PMIDs: 17204055, 20337973, 16602010).

Approved on: 2023-08-26

Published on: 2023-08-26

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