Variant: NM_000162.5(GCK):c.824G>A (p.Arg275His)

CA4239518

432386 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 9c256fff-60f0-4d8a-92bd-b19c0982e8d4

Approved on: 2023-11-23

Published on: 2023-11-23

HGVS expressions

NM_000162.5:c.824G>A
NM_000162.5(GCK):c.824G>A (p.Arg275His)
NC_000007.14:g.44147689C>T
CM000669.2:g.44147689C>T
NC_000007.13:g.44187288C>T
CM000669.1:g.44187288C>T
NC_000007.12:g.44153813C>T
NG_008847.1:g.46735G>A
NG_008847.2:g.55482G>A
ENST00000395796.8:c.*822G>A
ENST00000616242.5:c.824G>A
ENST00000345378.7:c.827G>A
ENST00000403799.8:c.824G>A
ENST00000671824.1:c.824G>A
ENST00000673284.1:c.824G>A
ENST00000345378.6:c.827G>A
ENST00000395796.7:c.821G>A
ENST00000403799.7:c.824G>A
ENST00000437084.1:c.773G>A
ENST00000616242.4:c.821G>A
NM_000162.3:c.824G>A
NM_033507.1:c.827G>A
NM_033508.1:c.821G>A
NM_000162.4:c.824G>A
NM_001354800.1:c.824G>A
NM_033507.2:c.827G>A
NM_033508.2:c.821G>A
NM_033507.3:c.827G>A
NM_033508.3:c.821G>A

Uncertain Significance

• Met criteria codes: PS4_Moderate PP2 PM2_Supporting PM5_Supporting

• Not Met criteria codes: BP4 PS3 PP3 BS3 BS1

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.824G>A variant in the glucokinase gene, GCK, causes an amino acid change of arginine to histidine at codon 275 (p.(Arg275His)) of NM_000162.5. This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002940 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting). 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 has a REVEL score of 0.545, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function. While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30592380). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4_Moderate; PMID: 30592380, internal lab contributors). Another missense variant, c.823C>T p.Arg275His, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275His (PM5_Supporting). In summary, c.824G>A 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): PS4_Moderate, PP2, PM2_Supporting, PM5_Supporting.

Met criteria codes

• PS4_Moderate: This variant was identified in 4 unrelated individuals with hyperglycemia; (PS4_Moderate; PMID: 30592380, 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).
• PM2_Supporting: This variant has a gnomAD v2.1.1 Popmax filtering allele frequency of 0.000002940 (below the MDEP threshold of 0.000003) and ≤ 2 copies observed in the European non-Finnish population and ≤ 1 copy in any other subpopulation, thereby meeting the ClinGen MDEP criteria for PM2_Supporting (PM2_Supporting).
• PM5_Supporting: Another missense variant, c.823C>T p.Arg275His, has been classified as pathogenic by the ClinGen MDEP but has a greater Grantham distance than p.Arg275His (PM5_Supporting).

Not Met criteria codes

• BP4: This variant has a REVEL score of 0.545, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.
• PS3: While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30592380).
• PP3: This variant has a REVEL score of 0.545, which is between the ClinGen MDEP thresholds, predicting neither a damaging nor benign impact on GCK function.
• BS3: While studies exploring the effect of this variant on protein function have been performed, these studies do not meet the criteria set forth by the MDEP for the application of PS3 or BS3 (PMID: 30592380).
• BS1: The Popmax filtering allele frequency of the c.824G>A variant in gnomAD v2.1.1 is 0.00002940, which falls between ClinGen MDEP-established cutoffs for PM2_Supporting and BS1; thus, neither criterion will be applied.