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]

Variant: NM_000162.5(GCK):c.1348G>T (p.Ala450Ser)

CA367396909

1770532 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 006063e7-216f-4dcf-be85-7f23491044ab

Approved on: 2026-04-17

Published on: 2026-04-28

HGVS expressions

NM_000162.5:c.1348G>T

NM_000162.5(GCK):c.1348G>T (p.Ala450Ser)

NC_000007.14:g.44145186C>A

CM000669.2:g.44145186C>A

NC_000007.13:g.44184785C>A

CM000669.1:g.44184785C>A

NC_000007.12:g.44151310C>A

NG_008847.1:g.49238G>T

NG_008847.2:g.57985G>T

ENST00000395796.8:c.*1346G>T

ENST00000616242.5:c.*468G>T

ENST00000683378.1:n.574G>T

ENST00000336642.9:c.382G>T

ENST00000345378.7:c.1351G>T

ENST00000403799.8:c.1348G>T

ENST00000671824.1:c.1411G>T

ENST00000672743.1:n.360G>T

ENST00000673284.1:c.1348G>T

ENST00000336642.8:c.400G>T

ENST00000345378.6:c.1351G>T

ENST00000395796.7:c.1345G>T

ENST00000403799.7:c.1348G>T

ENST00000437084.1:c.1297G>T

ENST00000459642.1:n.728G>T

ENST00000616242.4:c.1345G>T

NM_000162.3:c.1348G>T

NM_033507.1:c.1351G>T

NM_033508.1:c.1345G>T

NM_000162.4:c.1348G>T

NM_001354800.1:c.1348G>T

NM_001354801.1:c.337G>T

NM_001354802.1:c.208G>T

NM_001354803.1:c.382G>T

NM_033507.2:c.1351G>T

NM_033508.2:c.1345G>T

NM_033507.3:c.1351G>T

NM_033508.3:c.1345G>T

NM_001354803.2:c.382G>T

Likely Pathogenic

PS4_Moderate PP4_Moderate PP3 PP2 PS3_Moderate PM2_Supporting

PP1

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 3.1.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1348G>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to serine at codon 450 (p.(Ala450Ser)) 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 absent from gnomAD v4.1.0 (PM2_Supporting). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.848, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.01, which is below the MDEP cutoff (<0.5) (PS3_Moderate; PMID: 41516031). This variant was identified in three unrelated individuals with hyperglycemia; however, this number is below the ClinGen MDEP threshold for PS4_Moderate (PMID: 32370465, PMID: 35472491, PMID: 32375122, ClinVar: SCV004642448.3). One of these individuals did have a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3 mmol/L) (PP4_Moderate; PMID: 32370465). This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 32370465). In summary, c.1348G>T meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 3.1.0, approved 10/10/2025): PP2, PP3, PP4_Moderate, PM2_Supporting, PS3_Moderate.

PS4_Moderate

This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 32370465, PMID: 35472491, PMID: 32375122, ClinVar: SCV004642448.3]).

PP4_Moderate

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT with minimal increment (<3 mmol/L) (PP4_Moderate; PMID: 32370465).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.848, 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).

PS3_Moderate

MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.01, which is below the MDEP cutoff (<0.5) (PMID: 41516031).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PP1

This variant segregated with diabetes with one informative meioses in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 32370465).

Curation History

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