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.1133C>T (p.Ala378Val)

CA341585

21076 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: ee600241-27a2-46f8-8e47-92684c9a911a

HGVS expressions

NM_000162.5:c.1133C>T

NM_000162.5(GCK):c.1133C>T (p.Ala378Val)

NC_000007.14:g.44145617G>A

CM000669.2:g.44145617G>A

NC_000007.13:g.44185216G>A

CM000669.1:g.44185216G>A

NC_000007.12:g.44151741G>A

NG_008847.1:g.48807C>T

NG_008847.2:g.57554C>T

ENST00000395796.8:c.*1131C>T

ENST00000616242.5:c.*253C>T

ENST00000683378.1:n.359C>T

ENST00000336642.9:c.167C>T

ENST00000345378.7:c.1136C>T

ENST00000403799.8:c.1133C>T

ENST00000671824.1:c.1196C>T

ENST00000672743.1:n.145C>T

ENST00000673284.1:c.1133C>T

ENST00000336642.8:c.185C>T

ENST00000345378.6:c.1136C>T

ENST00000395796.7:c.1130C>T

ENST00000403799.7:c.1133C>T

ENST00000437084.1:c.1082C>T

ENST00000459642.1:n.513C>T

ENST00000616242.4:c.1130C>T

NM_000162.3:c.1133C>T

NM_033507.1:c.1136C>T

NM_033508.1:c.1130C>T

NM_000162.4:c.1133C>T

NM_001354800.1:c.1133C>T

NM_001354801.1:c.122C>T

NM_001354802.1:c.-8C>T

NM_001354803.1:c.167C>T

NM_033507.2:c.1136C>T

NM_033508.2:c.1130C>T

NM_033507.3:c.1136C>T

NM_033508.3:c.1130C>T

NM_001354803.2:c.167C>T

Pathogenic

PM2_Supporting PS4 PM3_Supporting PP1_Strong PP4 PP3 PP2 PM5

PM1

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 variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 378 (p.(Ala378Val)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.967, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in 9 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 14578306, 25935773, internal lab contributors). One of these individuals has a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (internal lab contributors). It has also been detected in an individual with neonatal diabetes who was homozygous for this variant and had antibody-negative diabetes (PM3_Supporting, PMID: 14578306). This variant also segregated with diabetes, with at least 4 informative meioses in 4 families with MODY (PP1_Strong; internal lab contributors). Additionally, another missense variant, c.1132G>A (p.Ala378Thr) has been interpreted as pathogenic by the ClinGen MDEP and p.Ala378Val has a greater Grantham distance (PM5). In summary, c.1133C>T meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PP1_Strong, PP4, PS4, PM5, PP2, PP3, PM2_Supporting, PM3_Supporting.

PM2_Supporting

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

PS4

This variant was identified in 9 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMIDs: 14578306, 25935773, internal lab contributors).

PM3_Supporting

This variant has been detected in an individual with neonatal diabetes who was homozygous for this variant and had negative antibodies (PM3_Supporting, PMID: 14578306)

PP1_Strong

This variant segregated with diabetes, with at least 4 informative meioses in 4 families with MODY (PP1_Strong; internal lab contributors).

PP4

This variant was identified in an individual with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (internal lab contributors).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.967, 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

Another missense variant, c.1132G>A (p.Ala378Thr) has been interpreted as pathogenic by the ClinGen MDEP and p.Ala378Val has a greater Grantham distance. (PM5).

PM1

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

Approved on: 2023-08-08

Published on: 2023-08-08

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