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.185T>C (p.Val62Ala)

CA367403278

585917 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

Link to MONDO

UUID: 7ecf85fd-61ba-4385-8e7e-4ef8c9f464ec

HGVS expressions

NM_000162.5:c.185T>C

NM_000162.5(GCK):c.185T>C (p.Val62Ala)

NC_000007.14:g.44153324A>G

CM000669.2:g.44153324A>G

NC_000007.13:g.44192923A>G

CM000669.1:g.44192923A>G

NC_000007.12:g.44159448A>G

NG_008847.1:g.41100T>C

NG_008847.2:g.49847T>C

ENST00000395796.8:c.*183T>C

ENST00000616242.5:c.185T>C

ENST00000682635.1:n.671T>C

ENST00000345378.7:c.188T>C

ENST00000403799.8:c.185T>C

ENST00000671824.1:c.185T>C

ENST00000673284.1:c.185T>C

ENST00000345378.6:c.188T>C

ENST00000395796.7:c.182T>C

ENST00000403799.7:c.185T>C

ENST00000437084.1:c.185T>C

ENST00000616242.4:c.182T>C

NM_000162.3:c.185T>C

NM_033507.1:c.188T>C

NM_033508.1:c.182T>C

NM_000162.4:c.185T>C

NM_001354800.1:c.185T>C

NM_033507.2:c.188T>C

NM_033508.2:c.182T>C

NM_033507.3:c.188T>C

NM_033508.3:c.182T>C

Likely Pathogenic

PP4_Moderate PP3 PP2 PM2_Supporting PP1_Moderate PM5

PS4

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.185T>C variant in the glucokinase gene, GCK, causes an amino acid change of valine to alanine at codon 62 (p.(Val62Ala)) 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 0.97, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable Popmax filtering allele frequency in gnomAD v2.1.1 due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African subpopulation, below the ClinGen MDEP threshold for PM2_Supporting (Popmax FAF ≤0.000003 and ≤ 2 copies in ENF and ≤1 copy in any other subpopulation) (PM2_Supporting). It was identified in at least two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18399931, PMID: 9736233, ClinVar ID: 585917). 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% and negative antibodies) (PP4_Moderate; PMID: 18399931). This variant segregated with diabetes, with four informative meioses in one family with MODY (PP1_Moderate; PMID: 9736233). Another missense variant, c.184G>A (p.Val62Met) has been interpreted as pathogenic by the ClinGen MDEP and p.Val62Ala has a greater Grantham distance (PM5). In summary, the c.185T>C variant meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP VCEP (specification version 1.3.0, approved 8/11/2023): PP4_Moderate, PP1_Moderate, PM5, PP2, PP3, PM2_Supporting.

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 negative antibodies) (PP4_Moderate; PMID: 18399931).

PP3

This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.97, 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).

PM2_Supporting

This variant has an incomputable Popmax filtering allele frequency due to 0 copies in the European non-Finnish subpopulation and 1 copy in the African subpopulation, below the ClinGen MDEP threshold for PM2_Supporting (Popmax FAF ≤0.000003 and ≤ 2 copies in ENF and ≤1 copy in any other subpopulation) (PM2_Supporting).

PP1_Moderate

This variant segregated with diabetes, with four informative meioses in one family with MODY (PP1_Moderate; PMID: 9736233).

PM5

Another missense variant, c.184G>A (p.Val62Met) has been interpreted as pathogenic by the ClinGen MDEP and p.Val62Ala has a greater Grantham distance (PM5).

PS4

This variant was identified in at least two unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (PMID: 18399931, PMID: 9736233, ClinVar ID: 585917).

Approved on: 2023-12-08

Published on: 2023-12-08

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