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.152G>C

CA4239428

Gene: GCK (HGNC:2645)

Condition: monogenic diabetes (MONDO:0015967)

Inheritance Mode: Semidominant inheritance

UUID: ddd7c361-8fce-47a0-a83b-6edc0ee0f8b9

Approved on: 2026-04-17

Published on: 2026-04-28

HGVS expressions

NM_001354803.2:c.152G>C

NC_000007.14:g.44145632C>G

CM000669.2:g.44145632C>G

NC_000007.13:g.44185231C>G

CM000669.1:g.44185231C>G

NC_000007.12:g.44151756C>G

NG_008847.1:g.48792G>C

NG_008847.2:g.57539G>C

ENST00000395796.8:c.*1116G>C

ENST00000616242.5:c.*238G>C

ENST00000683378.1:n.344G>C

ENST00000336642.9:c.152G>C

ENST00000345378.7:c.1121G>C

ENST00000403799.8:c.1118G>C

ENST00000671824.1:c.1181G>C

ENST00000672743.1:n.130G>C

ENST00000673284.1:c.1118G>C

ENST00000336642.8:c.170G>C

ENST00000345378.6:c.1121G>C

ENST00000395796.7:c.1115G>C

ENST00000403799.7:c.1118G>C

ENST00000437084.1:c.1067G>C

ENST00000459642.1:n.498G>C

ENST00000616242.4:c.1115G>C

NM_000162.3:c.1118G>C

NM_033507.1:c.1121G>C

NM_033508.1:c.1115G>C

NM_000162.4:c.1118G>C

NM_001354800.1:c.1118G>C

NM_001354801.1:c.107G>C

NM_001354802.1:c.-23G>C

NM_001354803.1:c.152G>C

NM_033507.2:c.1121G>C

NM_033508.2:c.1115G>C

NM_000162.5:c.1118G>C

NM_033507.3:c.1121G>C

NM_033508.3:c.1115G>C

Likely Pathogenic

PP1_Strong BS3_Supporting PP2 PP4_Moderate

PM5 PM2 BS1 BP4 PS4 PP3

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.1118G>C variant in the glucokinase gene, GCK, causes an amino acid change of serine to threonine at codon 373 (p.(Ser373Thr)) 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 has a Grpmax filtering allele frequency of 0.0000143 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied. This variant has a REVEL score of 0.504, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function. This variant was identified in 8 unrelated individuals with hyperglycemia; however, PS4 cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID: 36257325, internal lab contributors). At least 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 multiple values of mild fasting hyperglycemia) (PP4_Moderate; internal lab contributors). This variant segregated with hyperglycemia with four informative meioses in four families (PP1_Strong; PMID: 34556497, internal lab contributors). Functional studies that met MDEP wild type quality control measures demonstrated that the p.Ser373Thr variant does not result in impaired GCK protein function (RAI >0.5, RSI >0.5, and no impact on GKRP/GKA interaction) (BS3_Supporting; PMID: 41516031). Another missense variant at the same residue, c.1118G>A p.(Ser373Asn), has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied. In summary, c.1118G>C 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): PP1_Strong, PP2, PP4_Moderate, BS3_Supporting.

PP1_Strong

This variant segregated with hyperglycemia with four informative meioses in four families (PP1_Strong; PMID: 34556497, internal lab contributors).

BS3_Supporting

Functional studies that met MDEP wild type quality control measures demonstrated that the p.Ser373Thr variant does not result in impaired GCK protein function (RAI >0.5, RSI >0.5, and no impact on GKRP/GKA interaction) (BS3_Supporting; PMID: 41516031)

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_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 multiple values of mild fasting hyperglycemia) (PP4_Moderate; internal lab contributors).

PM5

Another missense variant, [c.1118G>A p.(Ser373Asn)] has been classified as a VUS by the ClinGen MDEP; therefore, PM5 will not be applied.

PM2

This variant has a Grpmax filtering allele frequency of 0.0000143 in gnomAD v4.1.0, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.

BS1

BP4

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PS4

This variant was identified in 7 unrelated individuals with hyperglycemia; however, PS4 cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID: 36257325, internal lab contributors).

PP3

This variant has a REVEL score of 0.504, which is between the ClinGen MDEP thresholds for BP4 and PP3, predicting neither a damaging nor benign impact on GCK function.

Curation History

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