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Variant: NM_001354803.2:c.407_418del

CA2017997780

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
UUID: 5aea8eca-05ef-4eac-8699-86aa13e05d51

HGVS expressions

NM_001354803.2:c.407_418del
NC_000007.14:g.44145158_44145169del
CM000669.2:g.44145158_44145169del
NC_000007.13:g.44184757_44184768del
CM000669.1:g.44184757_44184768del
NC_000007.12:g.44151282_44151293del
NG_008847.1:g.49263_49274del
NG_008847.2:g.58010_58021del
ENST00000395796.8:c.*1371_*1382del
ENST00000616242.5:c.*493_*504del
ENST00000683378.1:n.599_610del
ENST00000336642.9:c.407_418del
ENST00000345378.7:c.1376_1387del
ENST00000403799.8:c.1373_1384del
ENST00000671824.1:c.1436_1447del
ENST00000672743.1:n.381+4_381+15del
ENST00000673284.1:c.1369+4_1369+15del
ENST00000336642.8:n.425_436del
ENST00000345378.6:c.1376_1387del
ENST00000395796.7:c.1370_1381del
ENST00000403799.7:c.1373_1384del
ENST00000437084.1:c.1322_1333del
ENST00000459642.1:n.753_764del
ENST00000616242.4:n.1370_1381del
NM_000162.3:c.1373_1384del
NM_033507.1:c.1376_1387del
NM_033508.1:c.1370_1381del
NM_000162.4:c.1373_1384del
NM_001354800.1:c.1369+4_1369+15del
NM_001354801.1:c.362_373del
NM_001354802.1:c.229+4_229+15del
NM_001354803.1:c.407_418del
NM_033507.2:c.1376_1387del
NM_033508.2:c.1370_1381del
NM_000162.5:c.1373_1384del
NM_033507.3:c.1376_1387del
NM_033508.3:c.1370_1381del

Uncertain Significance

Met criteria codes 3
PP1_Moderate PM4 PM2_Supporting
Not Met criteria codes 2
PS4 PP4

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.1373_1384del variant in the glucokinase gene, GCK, is a 12 base pair deletion resulting in the in-frame deletion of 4 amino acids at codon 458 (p.(Lys458_Cys461del)) within exon 10 of NM_000162.5. The c.1373_1384del variant is predicted to change the length of the protein due an in-frame deletion of 4 amino acids in a nonrepeat region (PM4). Additionally, this variant is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in 3 unrelated individuals with non-autoimmune/insulin-deficient diabetes; however, this number does not meet the MDEP cutoff for PS4_Moderate (PMID: 30105470; internal lab contributor). This variant is present in an individual reported to have GCK-MODY; however, there was insufficient information to evaluate for PP4 (PMID: 30105470). This variant segregates with disease with 3 meioses in 2 families with MODY (PP1_Moderate; PMID 30105470). In summary, c.1373_1384del meets the criteria to be classified as VUS for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PM4, PM2_Supporting, PP1_Moderate.
Met criteria codes
PP1_Moderate
This variant segregates with disease with 3 meioses in 2 families with MODY (PP1_Moderate; PMID 30105470)
PM4
The c.1373_1384del variant is predicted to change the length of the protein due an in-frame deletion of 4 amino acids in a nonrepeat region (PM4)
PM2_Supporting
Absent from gnomAD v2.1.1 (PM2_Supporting)
Not Met criteria codes
PS4
3 cases (one from internal contributor, two from PMID 30105470)
PP4
Not enough clinical information to evaluate for PP4
Approved on: 2023-06-18
Published on: 2023-06-18
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