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_001354803.2:c.383C>T

CA367396903

2734986 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: b97ba4dd-43c9-40af-a27a-b470aea42cb3

Approved on: 2026-04-17

Published on: 2026-04-28

HGVS expressions

NM_001354803.2:c.383C>T

NC_000007.14:g.44145185G>A

CM000669.2:g.44145185G>A

NC_000007.13:g.44184784G>A

CM000669.1:g.44184784G>A

NC_000007.12:g.44151309G>A

NG_008847.1:g.49239C>T

NG_008847.2:g.57986C>T

ENST00000395796.8:c.*1347C>T

ENST00000616242.5:c.*469C>T

ENST00000683378.1:n.575C>T

ENST00000336642.9:c.383C>T

ENST00000345378.7:c.1352C>T

ENST00000403799.8:c.1349C>T

ENST00000671824.1:c.1412C>T

ENST00000672743.1:n.361C>T

ENST00000673284.1:c.1349C>T

ENST00000336642.8:c.401C>T

ENST00000345378.6:c.1352C>T

ENST00000395796.7:c.1346C>T

ENST00000403799.7:c.1349C>T

ENST00000437084.1:c.1298C>T

ENST00000459642.1:n.729C>T

ENST00000616242.4:c.1346C>T

NM_000162.3:c.1349C>T

NM_033507.1:c.1352C>T

NM_033508.1:c.1346C>T

NM_000162.4:c.1349C>T

NM_001354800.1:c.1349C>T

NM_001354801.1:c.338C>T

NM_001354802.1:c.209C>T

NM_001354803.1:c.383C>T

NM_033507.2:c.1352C>T

NM_033508.2:c.1346C>T

NM_000162.5:c.1349C>T

NM_033507.3:c.1352C>T

NM_033508.3:c.1346C>T

Likely Pathogenic

PP3 PP2 PM5_Supporting PS4_Moderate PM2_Supporting

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.1349C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 450 (p.(Ala450Val)) 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 0.921, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; [2 probands in PMID: 31638168, 1 family with 2 patients in PMID: 22035297 / PMID: 24918535, and 1 proband in PMID: 29207974]). Another missense variant at the same residue, [c.1348G>T (p.Ala450Ser)], has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1349C>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, PM2_Supporting, PM5_Supporting, PS4_Moderate.

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.921, 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).

PM5_Supporting

Another missense variant at the same residue, [c.1348G>T (p.Ala450Ser)], has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).

PS4_Moderate

This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; [2 probands in PMID: 31638168, 1 family with 2 patients in PMID: 22035297 / PMID: 24918535, and 1 proband in PMID: 29207974]).

PM2_Supporting

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

Curation History

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