Variant: NM_000162.5(GCK):c.1307T>A (p.Ile436Asn)

CA213751

36195 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 848bb6b5-a99b-41c3-a9b8-413c2dce18db

Approved on: 2024-04-27

Published on: 2024-04-27

HGVS expressions

NM_000162.5:c.1307T>A
NM_000162.5(GCK):c.1307T>A (p.Ile436Asn)
NC_000007.14:g.44145227A>T
CM000669.2:g.44145227A>T
NC_000007.13:g.44184826A>T
CM000669.1:g.44184826A>T
NC_000007.12:g.44151351A>T
NG_008847.1:g.49197T>A
NG_008847.2:g.57944T>A
ENST00000395796.8:c.*1305T>A
ENST00000616242.5:c.*427T>A
ENST00000683378.1:n.533T>A
ENST00000336642.9:c.341T>A
ENST00000345378.7:c.1310T>A
ENST00000403799.8:c.1307T>A
ENST00000671824.1:c.1370T>A
ENST00000672743.1:n.319T>A
ENST00000673284.1:c.1307T>A
ENST00000336642.8:c.359T>A
ENST00000345378.6:c.1310T>A
ENST00000395796.7:c.1304T>A
ENST00000403799.7:c.1307T>A
ENST00000437084.1:c.1256T>A
ENST00000459642.1:n.687T>A
ENST00000616242.4:c.1304T>A
NM_000162.3:c.1307T>A
NM_033507.1:c.1310T>A
NM_033508.1:c.1304T>A
NM_000162.4:c.1307T>A
NM_001354800.1:c.1307T>A
NM_001354801.1:c.296T>A
NM_001354802.1:c.167T>A
NM_001354803.1:c.341T>A
NM_033507.2:c.1310T>A
NM_033508.2:c.1304T>A
NM_033507.3:c.1310T>A
NM_033508.3:c.1304T>A
NM_001354803.2:c.341T>A

Pathogenic

• Met criteria codes: PP4_Moderate PS4_Moderate PP3 PP2 PP1_Strong PM5_Supporting PM2_Supporting PS3_Supporting

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.1307T>A variant in the glucokinase gene, GCK, causes an amino acid change of isoleucine to asparagine at codon 436 (p.(Ile436Asn)) 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 also predicted to be deleterious by computational evidence, with a REVEL score of 0.957, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant is absent in gnomAD v2.1.1 (PM2_Supporting), and was identified in at least 5 unrelated individuals with hyperglycemia (PS4_Moderate; PMID 17204055, PMID 20337973, PMID 22493702, internal lab contributors). At least 2 of these individuals have a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies +/- 2 hour oral glucose tolerance test increment <3 mmol/L) (PP4_Moderate; internal lab contributors). This variant also segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors). Another missense variant, c.1306A>T p.Ile436Phe has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting). While the RAI of this variant was 0.975, this variant results in decreased inhibition by GKRP (PS3_Supporting; PMID: 22493702). In summary, this evidence supports the classification of c.1307T>A as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PP1_Strong, PS4_Moderate, PP4_Moderate, PM5_Supporting, PP2, PP3, PM2_Supporting.

Met criteria codes

• PP4_Moderate: This variant was identified in 2 unrelated individuals with a clinical history highly specific for GCK-hyperglycemia (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and negative antibodies +/- 2 hour oral glucose tolerance test increment <3 mmol/L).
• PS4_Moderate: This variant was identified in at least 5 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4; PMID 17204055, PMID 20337973, PMID 22493702, internal lab contributors).
• PP3: This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.957, 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).
• PP1_Strong: This variant segregated with diabetes/hyperglycemia, with 4 informative meioses in 2 families (PP1_Strong; internal lab contributors).
• PM5_Supporting: Another missense variant, c.1306A>T p.Ile436Phe has been interpreted as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PS3_Supporting: While the relative activity index (RAI) of this variant was above the MDEP cutoff of 0.5, and a relative stability index (RSI) was not calculated, the variant did exhibit marked thermal instability as well as decreased inhibition by GKRP (PS3_Supporting).