Variant: NM_000162.5(GCK):c.1280_1283dup (p.Arg429fs)

CA1139660055

995103 (ClinVar)

Gene: GCK

Condition: maturity-onset diabetes of the young type 2

Inheritance Mode: Semidominant inheritance

UUID: 06ec1ad0-a52d-4f2c-8dab-878211c0d73b

Approved on: 2023-11-03

Published on: 2023-11-03

HGVS expressions

NM_000162.5:c.1280_1283dup
NM_000162.5(GCK):c.1280_1283dup (p.Arg429fs)
NC_000007.14:g.44145254_44145257dup
CM000669.2:g.44145254_44145257dup
NC_000007.13:g.44184853_44184856dup
CM000669.1:g.44184853_44184856dup
NC_000007.12:g.44151378_44151381dup
NG_008847.1:g.49170_49173dup
NG_008847.2:g.57917_57920dup
ENST00000395796.8:c.*1278_*1281dup
ENST00000616242.5:c.*400_*403dup
ENST00000683378.1:n.506_509dup
ENST00000336642.9:c.314_317dup
ENST00000345378.7:c.1283_1286dup
ENST00000403799.8:c.1280_1283dup
ENST00000671824.1:c.1343_1346dup
ENST00000672743.1:n.292_295dup
ENST00000673284.1:c.1280_1283dup
ENST00000336642.8:c.332_335dup
ENST00000345378.6:c.1283_1286dup
ENST00000395796.7:c.1277_1280dup
ENST00000403799.7:c.1280_1283dup
ENST00000437084.1:c.1229_1232dup
ENST00000459642.1:n.660_663dup
ENST00000616242.4:c.1277_1280dup
NM_000162.3:c.1280_1283dup
NM_033507.1:c.1283_1286dup
NM_033508.1:c.1277_1280dup
NM_000162.4:c.1280_1283dup
NM_001354800.1:c.1280_1283dup
NM_001354801.1:c.269_272dup
NM_001354802.1:c.140_143dup
NM_001354803.1:c.314_317dup
NM_033507.2:c.1283_1286dup
NM_033508.2:c.1277_1280dup
NM_033507.3:c.1283_1286dup
NM_033508.3:c.1277_1280dup
NM_001354803.2:c.314_317dup

Likely Pathogenic

• Met criteria codes: PM2_Supporting PVS1

• Not Met criteria codes: PS4 PP4

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.1280_1283dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 429 (NM_000162.5), adding 31 novel amino acids before encountering a stop codon (p.(Arg429AlafsTer31)). 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 is absent in gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, c.1280_1283dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).
• PVS1: Frameshift in exon 10While 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).

Not Met criteria codes

• PS4: One case at a clinical testing laboratory
• PP4: This variant was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to insufficient clinical information (internal lab contributors).