Variant: NM_000162.3(GCK):c.1255_1264delTTCAAGGAGC

CA915948961

817706 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: de7ed781-507f-4044-afb4-2a10ddc43541

Approved on: 2023-06-20

Published on: 2023-06-20

HGVS expressions

NM_000162.3(GCK):c.1255_1264delTTCAAGGAGC
NC_000007.14:g.44145273_44145282del
CM000669.2:g.44145273_44145282del
NC_000007.13:g.44184872_44184881del
CM000669.1:g.44184872_44184881del
NC_000007.12:g.44151397_44151406del
NG_008847.1:g.49145_49154del
NG_008847.2:g.57892_57901del
ENST00000395796.8:c.*1253_*1262del
ENST00000616242.5:c.*375_*384del
ENST00000683378.1:n.481_490del
ENST00000336642.9:c.289_298del
ENST00000345378.7:c.1258_1267del
ENST00000403799.8:c.1255_1264del
ENST00000671824.1:c.1318_1327del
ENST00000672743.1:n.267_276del
ENST00000673284.1:c.1255_1264del
ENST00000336642.8:n.307_316del
ENST00000345378.6:c.1258_1267del
ENST00000395796.7:c.1252_1261del
ENST00000403799.7:c.1255_1264del
ENST00000437084.1:c.1204_1213del
ENST00000459642.1:n.635_644del
ENST00000616242.4:n.1252_1261del
NM_000162.3:c.1255_1264del
NM_033507.1:c.1258_1267del
NM_033508.1:c.1252_1261del
NM_000162.4:c.1255_1264del
NM_001354800.1:c.1255_1264del
NM_001354801.1:c.244_253del
NM_001354802.1:c.115_124del
NM_001354803.1:c.289_298del
NM_033507.2:c.1258_1267del
NM_033508.2:c.1252_1261del
NM_000162.5:c.1255_1264del
NM_033507.3:c.1258_1267del
NM_033508.3:c.1252_1261del
NM_001354803.2:c.289_298del

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 1.0.0

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1255_1264delTTCAAGGAGC variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 419 (NM_000162.5), adding 9 novel amino acids before encountering a stop codon (p.(F419GfsX9)). 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.1255_1264delTTCAAGGAGC meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.2.0, approved 6/7/2023): PVS1, PM2_supporting.

Met criteria codes

• PM2_Supporting: This variant is 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).

Not Met criteria codes

• PS4: One case (GeneDx)
• 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).