Variant: NM_001354803.2:c.373dup

CA2017997774

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: f5e11f12-31e0-43fe-977d-c6bd48a3ceb8

Approved on: 2023-06-25

Published on: 2023-06-25

HGVS expressions

NM_001354803.2:c.373dup
NC_000007.14:g.44145196dup
CM000669.2:g.44145196dup
NC_000007.13:g.44184795dup
CM000669.1:g.44184795dup
NC_000007.12:g.44151320dup
NG_008847.1:g.49229dup
NG_008847.2:g.57976dup
ENST00000395796.8:c.*1337dup
ENST00000616242.5:c.*459dup
ENST00000683378.1:n.565dup
ENST00000336642.9:c.373dup
ENST00000345378.7:c.1342dup
ENST00000403799.8:c.1339dup
ENST00000671824.1:c.1402dup
ENST00000672743.1:n.351dup
ENST00000673284.1:c.1339dup
ENST00000336642.8:n.391dup
ENST00000345378.6:c.1342dup
ENST00000395796.7:c.1336dup
ENST00000403799.7:c.1339dup
ENST00000437084.1:c.1288dup
ENST00000459642.1:n.719dup
ENST00000616242.4:n.1336dup
NM_000162.3:c.1339dup
NM_033507.1:c.1342dup
NM_033508.1:c.1336dup
NM_000162.4:c.1339dup
NM_001354800.1:c.1339dup
NM_001354801.1:c.328dup
NM_001354802.1:c.199dup
NM_001354803.1:c.373dup
NM_033507.2:c.1342dup
NM_033508.2:c.1336dup
NM_000162.5:c.1339dup
NM_033507.3:c.1342dup
NM_033508.3:c.1336dup

Pathogenic

• Met criteria codes: PVS1 PP4_Moderate PM2_Supporting

• Not Met criteria codes: PS4 PP1

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.1339dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 447 (NM_000162.5), adding 12 novel amino acids before encountering a stop codon (p.(Arg447ProfsTer12)). 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). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). 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 a three generation family history of diabetes) (PP4_Moderate, internal lab contributor). While this variant was identified in one individual with diabetes, this does not meet the MDEP cutoff for PS4_Moderate. Additionally, this variant segregated with disease with one informative meiosis in this individual's family, however this does not meet the thresholds for PP1 set by Jarvik and Browning (PMID: 27236918) (internal lab contributor). In summary, the c.1339dup 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 6/7/2023x): PVS1, PP4_Moderate, PM2_Supporting.

Met criteria codes

• 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).
• 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 a three generation family history of diabetes) (PP4_Moderate, internal lab contributor).
• PM2_Supporting: Absent in gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: One case from internal lab contributor
• PP1: One meiosis in one family from internal lab contributor