Variant: NM_001354803.2:c.369_379del

CA2017997773

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 99e42b10-74bf-4107-b450-2483519771d4

Approved on: 2023-06-25

Published on: 2023-06-25

HGVS expressions

NM_001354803.2:c.369_379del
NC_000007.14:g.44145190_44145200del
CM000669.2:g.44145190_44145200del
NC_000007.13:g.44184789_44184799del
CM000669.1:g.44184789_44184799del
NC_000007.12:g.44151314_44151324del
NG_008847.1:g.49225_49235del
NG_008847.2:g.57972_57982del
ENST00000395796.8:c.*1333_*1343del
ENST00000616242.5:c.*455_*465del
ENST00000683378.1:n.561_571del
ENST00000336642.9:c.369_379del
ENST00000345378.7:c.1338_1348del
ENST00000403799.8:c.1335_1345del
ENST00000671824.1:c.1398_1408del
ENST00000672743.1:n.347_357del
ENST00000673284.1:c.1335_1345del
ENST00000336642.8:n.387_397del
ENST00000345378.6:c.1338_1348del
ENST00000395796.7:c.1332_1342del
ENST00000403799.7:c.1335_1345del
ENST00000437084.1:c.1284_1294del
ENST00000459642.1:n.715_725del
ENST00000616242.4:n.1332_1342del
NM_000162.3:c.1335_1345del
NM_033507.1:c.1338_1348del
NM_033508.1:c.1332_1342del
NM_000162.4:c.1335_1345del
NM_001354800.1:c.1335_1345del
NM_001354801.1:c.324_334del
NM_001354802.1:c.195_205del
NM_001354803.1:c.369_379del
NM_033507.2:c.1338_1348del
NM_033508.2:c.1332_1342del
NM_000162.5:c.1335_1345del
NM_033507.3:c.1338_1348del
NM_033508.3:c.1332_1342del

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP1_Moderate PP4

• Not Met criteria codes: PS4

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.1335_1345del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 8 novel amino acids before encountering a stop codon (p.(Arg447ProfsTer8)). 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; PMID: 19790256). Additionally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in one individual with a diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate. However, this individual has a clinical history highly specific for GCK-MODY (FBG 5.5-8 mmol/L and HbA1c 5.6 - 7.6%) (PP4; PMID: 14517956, internal lab contributor). This variant segregates with disease with 4 informative meiosis in this individual's family (PP1_moderate; internal lab contributor). In summary, the c.1335_1345del variant 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, PP1_moderate, PP4, PM2_Supporting.

Met criteria codes

• PM2_Supporting: Absent in gnomAD
• 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; PMID: 19790256)
• PP1_Moderate: This variant segregated with disease, with 4 informative meioses in one families with MODY (internal lab contributors).
• PP4: 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%) (PP4; PMID: 14517956, internal lab contributor).

Not Met criteria codes

• PS4: This variant was identified in one individual with a diabetes; however this number does not meet the MDEP cutoff for PS4_Moderate