NM_033508.3:c.562A>G

CA4239602

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: c0c9fcfa-bc03-44bb-97bc-ba5bc98fc5d4

Approved on: 2023-11-22

Published on: 2023-11-22

HGVS expressions

NM_033508.3:c.562A>G
NC_000007.14:g.44149983T>C
CM000669.2:g.44149983T>C
NC_000007.13:g.44189582T>C
CM000669.1:g.44189582T>C
NC_000007.12:g.44156107T>C
NG_008847.1:g.44441A>G
NG_008847.2:g.53188A>G
ENST00000395796.8:c.*563A>G
ENST00000616242.5:c.565A>G
ENST00000682635.1:n.1051A>G
ENST00000345378.7:c.568A>G
ENST00000403799.8:c.565A>G
ENST00000671824.1:c.565A>G
ENST00000673284.1:c.565A>G
ENST00000345378.6:c.568A>G
ENST00000395796.7:c.562A>G
ENST00000403799.7:c.565A>G
ENST00000437084.1:c.514A>G
ENST00000616242.4:c.562A>G
NM_000162.3:c.565A>G
NM_033507.1:c.568A>G
NM_033508.1:c.562A>G
NM_000162.4:c.565A>G
NM_001354800.1:c.565A>G
NM_033507.2:c.568A>G
NM_033508.2:c.562A>G
NM_000162.5:c.565A>G
NM_033507.3:c.568A>G

Uncertain Significance

• Met criteria codes: PP4_Moderate PM5_Supporting BS1 PP1 PP2

• Not Met criteria codes: PS4 PM2 PM1 PP3

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 1.3.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.565A>G variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to valine at codon 189 (p.Ile189Val) 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). Another missense variant, c.566T>C, p.Ille189Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ile189Val (PM5_Supporting). This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00006302, which is greater than the MDEP threshold for BS1 (0.00004) (BS1). This variant was identified in 11 unrelated individuals with hyperglycemia; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID: 32533685, PMID: 33565752, internal lab contributors). 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; internal lab contributors). This variant segregated with diabetes/hyperglycemia, with two informative meioses in two families (PP1; internal lab contributors). This variant has a REVEL score of 0.6499, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. In summary, c.565A>G meets the criteria to be classified as a variant of uncertain significance for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP2, PM5_Supporting, PP4_Moderate, PP1, BS1.

Met criteria codes

• 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; internal lab contributors).
• PM5_Supporting: p.Ile189Thr is pathogenic (Ile-Thr GD 89, Ile-Val GD 29)​ Another missense variant, c.566T>C p.Ile189Thr, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Ile189Val (PM5_Supporting).
• BS1: This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.00006302, which is greater than the MDEP threshold for BS1 (0.00004) (BS1).
• PP1: This variant segregated with diabetes/hyperglycemia, with two informative meioses in two families (PP1; internal lab contributors).
• 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).

Not Met criteria codes

• PS4: This variant was identified in 11 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because the variant does not meet the PM2_Supporting cutoff (PMID: 32533685, PMID: 33565752, internal lab contributors).
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: This variant has a REVEL score of 0.6499, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.