Variant: NM_001354803.2:c.337_340dup

CA2573106066

Gene: GCK

Condition: maturity-onset diabetes of the young type 2

Inheritance Mode: Semidominant inheritance

UUID: 4f3d3b7c-fd4c-4918-977f-bc394d864500

Approved on: 2023-09-08

Published on: 2023-09-08

HGVS expressions

NM_001354803.2:c.337_340dup
NC_000007.14:g.44145228_44145231dup
CM000669.2:g.44145228_44145231dup
NC_000007.13:g.44184827_44184830dup
CM000669.1:g.44184827_44184830dup
NC_000007.12:g.44151352_44151355dup
NG_008847.1:g.49193_49196dup
NG_008847.2:g.57940_57943dup
ENST00000395796.8:c.*1301_*1304dup
ENST00000616242.5:c.*423_*426dup
ENST00000683378.1:n.529_532dup
ENST00000336642.9:c.337_340dup
ENST00000345378.7:c.1306_1309dup
ENST00000403799.8:c.1303_1306dup
ENST00000671824.1:c.1366_1369dup
ENST00000672743.1:n.315_318dup
ENST00000673284.1:c.1303_1306dup
ENST00000336642.8:n.355_358dup
ENST00000345378.6:c.1306_1309dup
ENST00000395796.7:c.1300_1303dup
ENST00000403799.7:c.1303_1306dup
ENST00000437084.1:c.1252_1255dup
ENST00000459642.1:n.683_686dup
ENST00000616242.4:n.1300_1303dup
NM_000162.3:c.1303_1306dup
NM_033507.1:c.1306_1309dup
NM_033508.1:c.1300_1303dup
NM_000162.4:c.1303_1306dup
NM_001354800.1:c.1303_1306dup
NM_001354801.1:c.292_295dup
NM_001354802.1:c.163_166dup
NM_001354803.1:c.337_340dup
NM_033507.2:c.1306_1309dup
NM_033508.2:c.1300_1303dup
NM_000162.5:c.1303_1306dup
NM_033507.3:c.1306_1309dup
NM_033508.3:c.1300_1303dup

Likely Pathogenic

• Met criteria codes: PVS1 PM2_Supporting

• Not Met criteria codes: 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.1303_1306dup variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 436 (NM_000162.5), adding 24 novel amino acids before encountering a stop codon (p.(Ile436ArgfsTer24)). 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 a clinical history highly consistent with GCK-MODY, but there was insufficient clinical information to evaluate for PP4 (internal lab contributors). In summary, c.1303_1306dup meets the criteria to be classified as likely pathogenic for monogenic diabetes. ACMG/AMP criteria applied, as specified by the ClinGen MDEP (specification version 1.3.0, approved 8/11/2023): 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).
• PM2_Supporting: This variant is absent in gnomAD v2.1.1 (PM2_Supporting).

Not Met criteria codes

• PP4: This variant was identified in an individual with a clinical history highly consistent with GCK-MODY, but there was insufficient clinical information to evaluate for PP4) (internal lab contributors).