The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document


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
More

Pathogenic

Met criteria codes 3
PM2_Supporting PVS1 PP4_Moderate
Not Met criteria codes 2
PS4 PP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.2.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
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
PM2_Supporting
Absent in gnomAD v2.1.1 (PM2_Supporting).
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).
Not Met criteria codes
PS4
One case from internal lab contributor
PP1
One meiosis in one family from internal lab contributor
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.