Variant: NM_001354803.2:c.413_*2del

CA2497028747

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Semidominant inheritance

UUID: e4760b38-7342-4953-a4bf-e8f7fcc34093

HGVS expressions

NM_001354803.2:c.413_*2del
NC_000007.14:g.44145134_44145155del
CM000669.2:g.44145134_44145155del
NC_000007.13:g.44184733_44184754del
CM000669.1:g.44184733_44184754del
NC_000007.12:g.44151258_44151279del
NG_008847.1:g.49269_49290del
NG_008847.2:g.58016_58037del
ENST00000395796.8:c.*1377_*1398del
ENST00000616242.5:c.*499_*520del
ENST00000683378.1:n.605_626del
ENST00000336642.9:c.413_*2del
ENST00000345378.7:c.1382_*2del
ENST00000403799.8:c.1379_*2del
ENST00000671824.1:c.1442_*2del
ENST00000672743.1:n.381+10_381+31del
ENST00000673284.1:c.1369+10_1369+31del
ENST00000336642.8:n.431_452del
ENST00000345378.6:c.1382_*2del
ENST00000395796.7:c.1376_*2del
ENST00000403799.7:c.1379_*2del
ENST00000437084.1:c.1328_*2del
ENST00000459642.1:n.759_780del
ENST00000616242.4:n.1376_1397del
NM_000162.3:c.1379_*2del
NM_033507.1:c.1382_*2del
NM_033508.1:c.1376_*2del
NM_000162.4:c.1379_*2del
NM_001354800.1:c.1369+10_1369+31del
NM_001354801.1:c.368_*2del
NM_001354802.1:c.229+10_229+31del
NM_001354803.1:c.413_*2del
NM_033507.2:c.1382_*2del
NM_033508.2:c.1376_*2del
NM_000162.5:c.1379_*2del
NM_033507.3:c.1382_*2del
NM_033508.3:c.1376_*2del

Likely Pathogenic

• Met criteria codes: PM2_Supporting PVS1

• Not Met criteria codes: PS4 PP4 PP1

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.1379_*2del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 460 (NM_000162.5), causing a deletion of amino acids 26-265 and adding 146 novel amino acids before encountering a stop codon (p.(p.Ala460_Gln465delins146)). 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 in gnomAD v2.1.1 (PM2_Supporting), and was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes. However, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor). Insufficient clinical information was available to evaluate for PP4. This variant segregated with diabetes with one informative meiosis in this individual's family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor). In summary, c.1379_*2del 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, approved 6/7/2023): PVS1, PM2_Supporting.

Met criteria codes

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

Not Met criteria codes

• PS4: This variant was identified in one individual with non-autoimmune and non-absolute/near-absolute insulin-deficient diabetes; however, PS4_Moderate cannot be applied because this number is below the ClinGen MDEP threshold (internal lab contributor).
• PP4: This variant was identified in an individual with diabetes; however, insufficient clinical information was available to evaluate for PP4 (internal lab contributor).
• PP1: This variant segregated with diabetes with one informative meiosis in a single family; however, this does not meet the thresholds for PP1 set by the ClinGen MDEP (PMID: 27236918, internal lab contributor).

Approved on: 2023-06-18

Published on: 2023-06-18