Variant: NM_000162.5(GCK):c.835G>C (p.Glu279Gln)

CA208420

211076 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 74d8f360-8f66-4226-92b9-8c48395cfbff

Approved on: 2023-06-21

Published on: 2023-06-21

HGVS expressions

NM_000162.5:c.835G>C
NM_000162.5(GCK):c.835G>C (p.Glu279Gln)
NC_000007.14:g.44147678C>G
CM000669.2:g.44147678C>G
NC_000007.13:g.44187277C>G
CM000669.1:g.44187277C>G
NC_000007.12:g.44153802C>G
NG_008847.1:g.46746G>C
NG_008847.2:g.55493G>C
ENST00000395796.8:c.*833G>C
ENST00000616242.5:c.835G>C
ENST00000345378.7:c.838G>C
ENST00000403799.8:c.835G>C
ENST00000671824.1:c.835G>C
ENST00000673284.1:c.835G>C
ENST00000345378.6:c.838G>C
ENST00000395796.7:c.832G>C
ENST00000403799.7:c.835G>C
ENST00000437084.1:c.784G>C
ENST00000616242.4:n.832G>C
NM_000162.3:c.835G>C
NM_033507.1:c.838G>C
NM_033508.1:c.832G>C
NM_000162.4:c.835G>C
NM_001354800.1:c.835G>C
NM_033507.2:c.838G>C
NM_033508.2:c.832G>C
NM_033507.3:c.838G>C
NM_033508.3:c.832G>C

Benign

• Met criteria codes: BA1 PP2

• Not Met criteria codes: PP3 PS4 PS3

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

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.835G>C variant in the glucokinase gene, GCK, causes an amino acid change of glutamic acid to glutamine at codon 279 (p.(Glu279Gln)) 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 has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000112, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1). This variant was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID 8446612, PMID 24097065, PMID 30245511, internal lab contributor). This variant has a REVEL score of 0.698, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function. While functional studies exploring the effect of this mutation on the gene have been assessed, these studies do not meet the criteria set forth by the MDEP for application of PS3 or BS3 (PMID: 8446612). In summary, c.835G>C meets the criteria to be classified as benign for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): BA1, PP2.

Met criteria codes

• BA1: This variant has a Popmax Filtering allele frequency in gnomAD 2.1.1 of 0.000112, which is greater than the MDEP threshold for BA1 (≥0.0001) (BA1).
• 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

• PP3: This variant has a REVEL score of 0.698, which is between the ClinGen MDEP thresholds predicting neither a damaging nor benign impact on GCK function.
• PS4: This variant was identified in at least 4 unrelated individuals with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4 cannot be applied because the variant MAF in gnomAD is above the ClinGen MDEP PM2_Supporting cutoff (PMID 8446612, PMID 24097065, PMID 30245511, internal lab contributor).
• PS3: While functional studies exploring the effect of this mutation on the gene have been assessed, these studies do not meet the criteria set forth by the MDEP for application of PS3 or BS3 (PMID: 8446612