Variant: NM_001354803.2:c.343_344del

CA2573106063

Gene: GCK

Condition: maturity-onset diabetes of the young type 2

Inheritance Mode: Semidominant inheritance

UUID: 2a9f8bfb-ccc6-426c-b0b6-937fac7cbde7

Approved on: 2023-06-25

Published on: 2023-06-25

HGVS expressions

NM_001354803.2:c.343_344del
NC_000007.14:g.44145225_44145226del
CM000669.2:g.44145225_44145226del
NC_000007.13:g.44184824_44184825del
CM000669.1:g.44184824_44184825del
NC_000007.12:g.44151349_44151350del
NG_008847.1:g.49199_49200del
NG_008847.2:g.57946_57947del
ENST00000395796.8:c.*1307_*1308del
ENST00000616242.5:c.*429_*430del
ENST00000683378.1:n.535_536del
ENST00000336642.9:c.343_344del
ENST00000345378.7:c.1312_1313del
ENST00000403799.8:c.1309_1310del
ENST00000671824.1:c.1372_1373del
ENST00000672743.1:n.321_322del
ENST00000673284.1:c.1309_1310del
ENST00000336642.8:n.361_362del
ENST00000345378.6:c.1312_1313del
ENST00000395796.7:c.1306_1307del
ENST00000403799.7:c.1309_1310del
ENST00000437084.1:c.1258_1259del
ENST00000459642.1:n.689_690del
ENST00000616242.4:n.1306_1307del
NM_000162.3:c.1309_1310del
NM_033507.1:c.1312_1313del
NM_033508.1:c.1306_1307del
NM_000162.4:c.1309_1310del
NM_001354800.1:c.1309_1310del
NM_001354801.1:c.298_299del
NM_001354802.1:c.169_170del
NM_001354803.1:c.343_344del
NM_033507.2:c.1312_1313del
NM_033508.2:c.1306_1307del
NM_000162.5:c.1309_1310del
NM_033507.3:c.1312_1313del
NM_033508.3:c.1306_1307del

Pathogenic

• Met criteria codes: PP4_Moderate PS4_Moderate PVS1 PM2_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 1.2.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1309_1310del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 437 (NM_000162.5), adding 21 novel amino acids before encountering a stop codon (p.(Thr437LeufsTer21)). While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1). This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and dominant family history of diabetes) (PP4_Moderate; internal lab contributors). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors). In summary, c.1309_1310del meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0 approved 6/7/2023): PVS1, PM2_supporting, PP4_moderate, PS4_Moderate.

Met criteria codes

• PP4_Moderate: This variant was identified in an individual with a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6% and dominant family history of diabetes) (PP4_Moderate; internal lab contributors).
• PS4_Moderate: This variant was identified in 4 unrelated individuals with non- autoimmune and non-absolute/near-absolute insulin-deficient diabetes (PS4_Moderate; internal lab contributors).
• PVS1: While this variant, located in exon 10 of 10, is predicted to cause a premature stop codon and to escape nonsense mediated decay, it is in a functionally important region of a gene where loss-of-function is an established disease mechanism (PVS1)
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).