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.1129C>A (p.Arg377Ser)

CA367398819

1727652 (ClinVar)

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: 3fd09c5a-7334-4761-a861-775841b44fdb

Approved on: 2026-10-29

Published on: 2026-10-29

HGVS expressions

NM_000162.5:c.1129C>A

NM_000162.5(GCK):c.1129C>A (p.Arg377Ser)

NC_000007.14:g.44145621G>T

CM000669.2:g.44145621G>T

NC_000007.13:g.44185220G>T

CM000669.1:g.44185220G>T

NC_000007.12:g.44151745G>T

NG_008847.1:g.48803C>A

NG_008847.2:g.57550C>A

ENST00000395796.8:c.*1127C>A

ENST00000616242.5:c.*249C>A

ENST00000683378.1:n.355C>A

ENST00000336642.9:c.163C>A

ENST00000345378.7:c.1132C>A

ENST00000403799.8:c.1129C>A

ENST00000671824.1:c.1192C>A

ENST00000672743.1:n.141C>A

ENST00000673284.1:c.1129C>A

ENST00000336642.8:c.181C>A

ENST00000345378.6:c.1132C>A

ENST00000395796.7:c.1126C>A

ENST00000403799.7:c.1129C>A

ENST00000437084.1:c.1078C>A

ENST00000459642.1:n.509C>A

ENST00000616242.4:c.1126C>A

NM_000162.3:c.1129C>A

NM_033507.1:c.1132C>A

NM_033508.1:c.1126C>A

NM_000162.4:c.1129C>A

NM_001354800.1:c.1129C>A

NM_001354801.1:c.118C>A

NM_001354802.1:c.-12C>A

NM_001354803.1:c.163C>A

NM_033507.2:c.1132C>A

NM_033508.2:c.1126C>A

NM_033507.3:c.1132C>A

NM_033508.3:c.1126C>A

NM_001354803.2:c.163C>A

Pathogenic

PP1_Strong PM5_Supporting PP3 PP2 PP4 PM2_Supporting PS4_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 3.1

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1129C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to proline at codon 377 (p.(Arg377Ser)) 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 0.988, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v4.1.2 (PM2_Supporting). This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 34746319, 35737141, internal lab contributors). Additionally, at least one of these individuals had a clinical history highly specific for GCK-hyperglycemia (FBG fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 34746319). This variant was segregated with hyperglycemia, with 6 informative meioses in two famlies (PP1_Strong; PMID: 34746319, internal lab contributors). Another missense variant at the same residue, c.1129C>T p.(Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377Ser (PM5_Supporting). In summary, this variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 3.1.0, approved 10/10/2025): PP2, PP3, PP4, PM2_Supporting, PS4_Moderate, PP1_Strong, PM5_Supporting.

PP1_Strong

This variant was segregated with hyperglycemia, with 6 informative meioses in two famlies (PP1_Strong; PMID: 34746319, internal lab contributors).

PM5_Supporting

Another missense variant, c.1129C>T p.Arg377Cys), has been classified as pathogenic by the ClinGen MDEP VCEP but has a greater Grantham distance than p.Arg377Ser (PM5_Supporting).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.988, 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).

PP4

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG fasting glucose 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 34746319).

PM2_Supporting

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

PS4_Moderate

This variant was identified in four unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 34746319, 35737141, internal lab contributors)

Curation History

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