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]

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Variant: NM_000162.5(GCK):c.184G>A (p.Val62Met)

CA16618472

419624 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 1f57faf8-0f13-448a-a462-a8cde367a841

HGVS expressions

NM_000162.5:c.184G>A

NM_000162.5(GCK):c.184G>A (p.Val62Met)

NC_000007.14:g.44153325C>T

CM000669.2:g.44153325C>T

NC_000007.13:g.44192924C>T

CM000669.1:g.44192924C>T

NC_000007.12:g.44159449C>T

NG_008847.1:g.41099G>A

NG_008847.2:g.49846G>A

ENST00000395796.8:c.*182G>A

ENST00000616242.5:c.184G>A

ENST00000682635.1:n.670G>A

ENST00000345378.7:c.187G>A

ENST00000403799.8:c.184G>A

ENST00000671824.1:c.184G>A

ENST00000673284.1:c.184G>A

ENST00000345378.6:c.187G>A

ENST00000395796.7:c.181G>A

ENST00000403799.7:c.184G>A

ENST00000437084.1:c.184G>A

ENST00000616242.4:n.181G>A

NM_000162.3:c.184G>A

NM_033507.1:c.187G>A

NM_033508.1:c.181G>A

NM_000162.4:c.184G>A

NM_001354800.1:c.184G>A

NM_033507.2:c.187G>A

NM_033508.2:c.181G>A

NM_033507.3:c.187G>A

NM_033508.3:c.181G>A

Pathogenic

PM2_Supporting PS3_Supporting PP4_Moderate PP1_Strong PP3 PP2 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 1.2.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.184G>A variant in the glucokinase gene, GCK, causes an amino acid change of valine to methionine at codon 62 (p.(Val62Met)) 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 0.972, which is greater than the MDEP VCEP threshold of 0.70 (PP3). While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID: 28726111, ClinVar ID: 419624, internal lab contributors). At least two of these individuals had a clinical history highly specific for for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479). This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID: 15677479). In summary, c.184G>A meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_strong, PP4_moderate, PS4_moderate, PP2, PP3, PM2_Supporting, PS3_Supporting.

PM2_Supporting

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

PS3_Supporting

While p.Val62Met did not have reduction in enzyme activity or stability, its activity was unresponsive to GKRP (PS3_Supporting; PMID 15677479).

PP4_Moderate

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% and OGTT increment < 3 mmol/L) (PP4_Moderate; PMID:15677479).

PP1_Strong

This variant segregated with diabetes, with six informative meioses in two families with MODY (PP1_Strong; PMID: 15677479).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.972, 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).

PS4_Moderate

This variant was identified in six unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; PMID:15677479, PMID: 28726111, ClinVar ID: 419624, internal lab contributors).

Approved on: 2023-08-25

Published on: 2023-08-25

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