Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_001354803.2:c.380_381del

CA2573105963

Gene: GCK

Condition: monogenic diabetes

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 2b7f985a-3da4-4d4e-a303-d439a0ea7e22

HGVS expressions

NM_001354803.2:c.380_381del

NC_000007.14:g.44145190_44145191del

CM000669.2:g.44145190_44145191del

NC_000007.13:g.44184789_44184790del

CM000669.1:g.44184789_44184790del

NC_000007.12:g.44151314_44151315del

NG_008847.1:g.49236_49237del

NG_008847.2:g.57983_57984del

ENST00000395796.8:c.*1344_*1345del

ENST00000616242.5:c.*466_*467del

ENST00000683378.1:n.572_573del

ENST00000336642.9:c.380_381del

ENST00000345378.7:c.1349_1350del

ENST00000403799.8:c.1346_1347del

ENST00000671824.1:c.1409_1410del

ENST00000672743.1:n.358_359del

ENST00000673284.1:c.1346_1347del

ENST00000336642.8:n.398_399del

ENST00000345378.6:c.1349_1350del

ENST00000395796.7:c.1343_1344del

ENST00000403799.7:c.1346_1347del

ENST00000437084.1:c.1295_1296del

ENST00000459642.1:n.726_727del

ENST00000616242.4:n.1343_1344del

NM_000162.3:c.1346_1347del

NM_033507.1:c.1349_1350del

NM_033508.1:c.1343_1344del

NM_000162.4:c.1346_1347del

NM_001354800.1:c.1346_1347del

NM_001354801.1:c.335_336del

NM_001354802.1:c.206_207del

NM_001354803.1:c.380_381del

NM_033507.2:c.1349_1350del

NM_033508.2:c.1343_1344del

NM_000162.5:c.1346_1347del

NM_033507.3:c.1349_1350del

NM_033508.3:c.1343_1344del

Likely Pathogenic

PM2_Supporting PVS1

PP4

Evidence Links 0

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

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Monogenic Diabetes VCEP

The c.1346_1347del variant in the glucokinase gene, GCK, causes a frameshift in the protein at codon 449 (NM_000162.5), adding 9 novel amino acids before encountering a premature stop codon (p.(Ala449GlyfsTer9)). 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; 19790256). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant was identified in an individual with diabetes/hyperglycemia; however, PP4 is unable to be evaluated due to lack of clinical information (PMID: 31638168). In summary, the c.1346_1347del 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 1.3.0, approved 8/11/2023): PVS1, PM2_Supporting.

PM2_Supporting

This variant is absent from 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; 19790256).

PP4

This variant was identified in an individual with diabetes/hyperglycemia; however, PP4 is unable to be evaluated due to lack of clinical information (PMID: 31638168).

Approved on: 2023-08-26

Published on: 2023-08-26

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