Variant: NM_000162.5(GCK):c.1278_1279del (p.Val427fs)

CA1139771800

1301411 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 044222ee-b66d-441c-9fca-cc0c7b94d742

Approved on: 2023-06-20

Published on: 2023-06-20

HGVS expressions

NM_000162.5:c.1278_1279del
NM_000162.5(GCK):c.1278_1279del (p.Val427fs)
NC_000007.14:g.44145256_44145257del
CM000669.2:g.44145256_44145257del
NC_000007.13:g.44184855_44184856del
CM000669.1:g.44184855_44184856del
NC_000007.12:g.44151380_44151381del
NG_008847.1:g.49168_49169del
NG_008847.2:g.57915_57916del
ENST00000395796.8:c.*1276_*1277del
ENST00000616242.5:c.*398_*399del
ENST00000683378.1:n.504_505del
ENST00000336642.9:c.312_313del
ENST00000345378.7:c.1281_1282del
ENST00000403799.8:c.1278_1279del
ENST00000671824.1:c.1341_1342del
ENST00000672743.1:n.290_291del
ENST00000673284.1:c.1278_1279del
ENST00000336642.8:n.330_331del
ENST00000345378.6:c.1281_1282del
ENST00000395796.7:c.1275_1276del
ENST00000403799.7:c.1278_1279del
ENST00000437084.1:c.1227_1228del
ENST00000459642.1:n.658_659del
ENST00000616242.4:n.1275_1276del
NM_000162.3:c.1278_1279del
NM_033507.1:c.1281_1282del
NM_033508.1:c.1275_1276del
NM_000162.4:c.1278_1279del
NM_001354800.1:c.1278_1279del
NM_001354801.1:c.267_268del
NM_001354802.1:c.138_139del
NM_001354803.1:c.312_313del
NM_033507.2:c.1281_1282del
NM_033508.2:c.1275_1276del
NM_033507.3:c.1281_1282del
NM_033508.3:c.1275_1276del
NM_001354803.2:c.312_313del

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: PP4 PS4

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.1278_1279del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 427 (NM_000162.5), adding 31 novel amino acids before encountering a stop codon (p.(Val427AlafsTer31)). 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 in gnomAD v2.1.1 (PM2_Supporting), and was identified in an individual with diabetes; however, PP4 is unable to be evaluated due to lack of clinical information (internal lab contributor). In summary, the c.1278_1279del variant 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

• 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).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PP4: Clinical information insufficient to evaluate for PP4
• PS4: One case (clinical information not available, internal lab collaborator)