Variant: NM_001354803.2:c.385del

CA2017997778

1708917 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 131be0ec-e128-4a7c-b984-27c08145387e

Approved on: 2023-06-20

Published on: 2023-06-20

HGVS expressions

NM_001354803.2:c.385del
NC_000007.14:g.44145185del
CM000669.2:g.44145185del
NC_000007.13:g.44184784del
CM000669.1:g.44184784del
NC_000007.12:g.44151309del
NG_008847.1:g.49241del
NG_008847.2:g.57988del
ENST00000395796.8:c.*1349del
ENST00000616242.5:c.*471del
ENST00000683378.1:n.577del
ENST00000336642.9:c.385del
ENST00000345378.7:c.1354del
ENST00000403799.8:c.1351del
ENST00000671824.1:c.1414del
ENST00000672743.1:n.363del
ENST00000673284.1:c.1351del
ENST00000336642.8:n.403del
ENST00000345378.6:c.1354del
ENST00000395796.7:c.1348del
ENST00000403799.7:c.1351del
ENST00000437084.1:c.1300del
ENST00000459642.1:n.731del
ENST00000616242.4:n.1348del
NM_000162.3:c.1351del
NM_033507.1:c.1354del
NM_033508.1:c.1348del
NM_000162.4:c.1351del
NM_001354800.1:c.1351del
NM_001354801.1:c.340del
NM_001354802.1:c.211del
NM_001354803.1:c.385del
NM_033507.2:c.1354del
NM_033508.2:c.1348del
NM_000162.5:c.1351del
NM_033507.3:c.1354del
NM_033508.3:c.1348del
NM_000162.5(GCK):c.1351del (p.Leu451fs)

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

• 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.1351del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 451 (NM_000162.5), adding 163 novel amino acids before encountering a stop codon (p.(Leu451TrpfsTer163)). This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which 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 two unrelated individuals with diabetes/elevated HbA1c; however, this number does not meet the MDEP cutoff for PS4_Moderate (internal lab contributors) One of these individuals has a clinical history suggestive of GCK-MODY; however, PP4 was unable to be evaluated due to insufficient clinical information (internal lab contributors). In summary, the c.1351del 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: This variant, located in exon 10 of 10, is predicted to cause loss of a stop codon and result in an elongated protein. The additional residues are expected to cause improper folding, resulting in loss of function in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID 19790256).
• PM2_Supporting: Absent in gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PS4: Two cases (internal lab contributors)
• PP4: Unable to calculate the MODY probability calculator for the two cases due to lack of treatment information.