Variant: NM_000162.5(GCK):c.1295_1297delinsGCCG (p.Pro432fs)

CA1139771354

1769182 (ClinVar)

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: 910862db-210f-4d7e-8621-37c105901d32

Approved on: 2023-09-08

Published on: 2023-09-08

HGVS expressions

NM_000162.5:c.1295_1297delinsGCCG
NM_000162.5(GCK):c.1295_1297delinsGCCG (p.Pro432fs)
NC_000007.14:g.44145237_44145239delinsCGGC
CM000669.2:g.44145237_44145239delinsCGGC
NC_000007.13:g.44184836_44184838delinsCGGC
CM000669.1:g.44184836_44184838delinsCGGC
NC_000007.12:g.44151361_44151363delinsCGGC
NG_008847.1:g.49185_49187delinsGCCG
NG_008847.2:g.57932_57934delinsGCCG
ENST00000395796.8:c.*1293_*1295delinsGCCG
ENST00000616242.5:c.*415_*417delinsGCCG
ENST00000683378.1:n.521_523delinsGCCG
ENST00000336642.9:c.329_331delinsGCCG
ENST00000345378.7:c.1298_1300delinsGCCG
ENST00000403799.8:c.1295_1297delinsGCCG
ENST00000671824.1:c.1358_1360delinsGCCG
ENST00000672743.1:n.307_309delinsGCCG
ENST00000673284.1:c.1295_1297delinsGCCG
ENST00000336642.8:n.347_349delinsGCCG
ENST00000345378.6:c.1298_1300delinsGCCG
ENST00000395796.7:c.1292_1294delinsGCCG
ENST00000403799.7:c.1295_1297delinsGCCG
ENST00000437084.1:c.1244_1246delinsGCCG
ENST00000459642.1:n.675_677delinsGCCG
ENST00000616242.4:n.1292_1294delinsGCCG
NM_000162.3:c.1295_1297delinsGCCG
NM_033507.1:c.1298_1300delinsGCCG
NM_033508.1:c.1292_1294delinsGCCG
NM_000162.4:c.1295_1297delinsGCCG
NM_001354800.1:c.1295_1297delinsGCCG
NM_001354801.1:c.284_286delinsGCCG
NM_001354802.1:c.155_157delinsGCCG
NM_001354803.1:c.329_331delinsGCCG
NM_033507.2:c.1298_1300delinsGCCG
NM_033508.2:c.1292_1294delinsGCCG
NM_033507.3:c.1298_1300delinsGCCG
NM_033508.3:c.1292_1294delinsGCCG
NM_001354803.2:c.329_331delinsGCCG

Pathogenic

• Met criteria codes: PM2_Supporting PVS1 PP1

• 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.1295_1297delinsCGGC variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 432 (NM_000162.5), adding 27 novel amino acids before encountering a stop codon (p.(Pro432ArgfsTer27)). 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). This variant was identified in an individual with a clinical history suggestive of GCK-hyperglycemia, but PP4 could not be evaluated due to insufficient clinical information (PMID 19150152). This variant segregated with diabetes with 3 informative meiosis in this individual's family (PP1; PMID 19150152). In summary, the c.1295_1297delinsGCCG variant meets the criteria to be classified as pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): PVS1, PP1, PM2_Supporting.

Met criteria codes

• PM2_Supporting: 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; PMID: 19790256).
• PP1: This variant segregated with diabetes, with 3 informative meioses in one family with MODY (PP1; PMID 19150152).

Not Met criteria codes

• PS4: 2 cases (1 in a clinical database, 1 in PMID 19150152)
• PP4: This variant was identified in an individual with a clinical history suggestive of GCK-hyperglycemia, but PP4 could not be evaluated due to insufficient clinical information (PMID 19150152).