Variant: NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr)

CA213740

36189 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: fa69a74e-6d24-423d-a24e-3ea3241ed013

Approved on: 2024-04-27

Published on: 2024-04-27

HGVS expressions

NM_000162.5:c.1268T>A
NM_000162.5(GCK):c.1268T>A (p.Phe423Tyr)
NC_000007.14:g.44145266A>T
CM000669.2:g.44145266A>T
NC_000007.13:g.44184865A>T
CM000669.1:g.44184865A>T
NC_000007.12:g.44151390A>T
NG_008847.1:g.49158T>A
NG_008847.2:g.57905T>A
ENST00000395796.8:c.*1266T>A
ENST00000616242.5:c.*388T>A
ENST00000683378.1:n.494T>A
ENST00000336642.9:c.302T>A
ENST00000345378.7:c.1271T>A
ENST00000403799.8:c.1268T>A
ENST00000671824.1:c.1331T>A
ENST00000672743.1:n.280T>A
ENST00000673284.1:c.1268T>A
ENST00000336642.8:c.320T>A
ENST00000345378.6:c.1271T>A
ENST00000395796.7:c.1265T>A
ENST00000403799.7:c.1268T>A
ENST00000437084.1:c.1217T>A
ENST00000459642.1:n.648T>A
ENST00000616242.4:c.1265T>A
NM_000162.3:c.1268T>A
NM_033507.1:c.1271T>A
NM_033508.1:c.1265T>A
NM_000162.4:c.1268T>A
NM_001354800.1:c.1268T>A
NM_001354801.1:c.257T>A
NM_001354802.1:c.128T>A
NM_001354803.1:c.302T>A
NM_033507.2:c.1271T>A
NM_033508.2:c.1265T>A
NM_033507.3:c.1271T>A
NM_033508.3:c.1265T>A
NM_001354803.2:c.302T>A

Pathogenic

• Met criteria codes: PP1_Moderate PP4_Moderate PM2_Supporting PS4 PP3 PP2

• Not Met criteria codes: BA1 BS1 BP4 BP1

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.1268T>A variant in the glucokinase gene, GCK, causes an amino acid change of phenylalanine to tyrosine at codon 423 (p.(Phe423Tyr)) 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 predicted to be deleterious by computational evidence, with a REVEL score of 0.801, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 23843579, 31968686, internal lab contributors). This variant segregated with hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 28012402, 23843579). 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 with minimal increment <3 mmol/l) (PP4_Moderate; PMID: 23843579). In summary, c.1268T>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): PS4, PP4_Moderate, PP1_Moderate, PM2_supporting, PP2, PP3.

Met criteria codes

• PP1_Moderate: This variant segregated with hyperglycemia, with three informative meioses in two families (PP1_Moderate; PMIDs: 28012402, 23843579).
• 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 with minimal increment <3 mmol/l) (PP4_Moderate; PMID: 23843579).
• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting). absent from gnomAD v4.0.0
• PS4: This variant was identified in eight unrelated individuals with hyperglycemia (PS4; PMIDs: 23843579, 31968686, internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.801, 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).

Not Met criteria codes

• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline