Variant: NM_000162.5(GCK):c.1361C>A (p.Ala454Glu)

CA16609264

393447 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 5373061c-5c70-4d02-bd9c-c75b82ee851e

Approved on: 2024-03-31

Published on: 2024-03-31

HGVS expressions

NM_000162.5:c.1361C>A
NM_000162.5(GCK):c.1361C>A (p.Ala454Glu)
NC_000007.14:g.44145173G>T
CM000669.2:g.44145173G>T
NC_000007.13:g.44184772G>T
CM000669.1:g.44184772G>T
NC_000007.12:g.44151297G>T
NG_008847.1:g.49251C>A
NG_008847.2:g.57998C>A
ENST00000395796.8:c.*1359C>A
ENST00000616242.5:c.*481C>A
ENST00000683378.1:n.587C>A
ENST00000336642.9:c.395C>A
ENST00000345378.7:c.1364C>A
ENST00000403799.8:c.1361C>A
ENST00000671824.1:c.1424C>A
ENST00000672743.1:n.373C>A
ENST00000673284.1:c.1361C>A
ENST00000336642.8:c.413C>A
ENST00000345378.6:c.1364C>A
ENST00000395796.7:c.1358C>A
ENST00000403799.7:c.1361C>A
ENST00000437084.1:c.1310C>A
ENST00000459642.1:n.741C>A
ENST00000616242.4:c.1358C>A
NM_000162.3:c.1361C>A
NM_033507.1:c.1364C>A
NM_033508.1:c.1358C>A
NM_000162.4:c.1361C>A
NM_001354800.1:c.1361C>A
NM_001354801.1:c.350C>A
NM_001354802.1:c.221C>A
NM_001354803.1:c.395C>A
NM_033507.2:c.1364C>A
NM_033508.2:c.1358C>A
NM_033507.3:c.1364C>A
NM_033508.3:c.1358C>A
NM_001354803.2:c.395C>A

Likely Pathogenic

• Met criteria codes: PM2_Supporting PS4_Moderate PS3_Moderate PP3 PP2

• Not Met criteria codes: PM1

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.1361C>A variant in the glucokinase gene, GCK, causes an amino acid change of alanine to glutamic acid at codon 454 (p.(Ala454Glu)) 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 0.965, which is greater than the MDEP VCEP threshold of 0.70 (PP3). MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.04, which is below the MDEP cutoff (<0.5) (PMID: 28842611). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 393447, PMIDs: 36257325, 20337973, 16602010, 17204055, internal lab contributors). In summary, c.1361C>A meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PS3_Moderate, PS4_Moderate, PP2, PP3, PM2_Supporting.

Met criteria codes

• PM2_Supporting: This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
• PS4_Moderate: This variant was identified in 6 unrelated individuals with hyperglycemia (PS4_Moderate; ClinVar: 393447, PMIDs: 36257325, 20337973, 16602010, 17204055, internal lab contributors).
• PS3_Moderate: MDEP wild type quality control measures were met, and the relative activity Index (RAI) of this variant was found to be 0.04, which is below the MDEP cutoff (<0.5) (PMID: 28842611).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.965, 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

• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline