Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • No ClinVar Id was directly found from the curated document
  • ClinVar Id was derived from the Allele Registry.
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

CA367396861

3068512 (ClinVar)

Gene: GCK
Condition: monogenic diabetes
Inheritance Mode: Semidominant inheritance
Link to MONDO
UUID: 307b183e-a302-43da-a3d3-517a4aee00a3
Approved on: 2024-03-31
Published on: 2024-03-31

HGVS expressions

NM_001354803.2:c.395C>T
NC_000007.14:g.44145173G>A
CM000669.2:g.44145173G>A
NC_000007.13:g.44184772G>A
CM000669.1:g.44184772G>A
NC_000007.12:g.44151297G>A
NG_008847.1:g.49251C>T
NG_008847.2:g.57998C>T
ENST00000395796.8:c.*1359C>T
ENST00000616242.5:c.*481C>T
ENST00000683378.1:n.587C>T
ENST00000336642.9:c.395C>T
ENST00000345378.7:c.1364C>T
ENST00000403799.8:c.1361C>T
ENST00000671824.1:c.1424C>T
ENST00000672743.1:n.373C>T
ENST00000673284.1:c.1361C>T
ENST00000336642.8:c.413C>T
ENST00000345378.6:c.1364C>T
ENST00000395796.7:c.1358C>T
ENST00000403799.7:c.1361C>T
ENST00000437084.1:c.1310C>T
ENST00000459642.1:n.741C>T
ENST00000616242.4:c.1358C>T
NM_000162.3:c.1361C>T
NM_033507.1:c.1364C>T
NM_033508.1:c.1358C>T
NM_000162.4:c.1361C>T
NM_001354800.1:c.1361C>T
NM_001354801.1:c.350C>T
NM_001354802.1:c.221C>T
NM_001354803.1:c.395C>T
NM_033507.2:c.1364C>T
NM_033508.2:c.1358C>T
NM_000162.5:c.1361C>T
NM_033507.3:c.1364C>T
NM_033508.3:c.1358C>T
More

Likely Pathogenic

Met criteria codes 5
PM2_Supporting PS4_Moderate PP2 PP3 PM5_Supporting
Not Met criteria codes 1
PM1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Monogenic Diabetes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GCK Version 1.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Monogenic Diabetes VCEP
The c.1361C>T variant in the glucokinase gene, GCK, causes an amino acid change of alanine to valine at codon 454 (p.(Ala454Val)) of NM_000162.5. GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2). This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.916, which is greater than the MDEP VCEP threshold of 0.70 (PP3). This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting). This variant was identified in 4 unrelated individuals with hyperglycemia (PS4; PMIDs: 34746319, 36257325). Another missense variant, c.1361C>A p.Ala454Glu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting). In summary, c.1361C>T 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): PS4_Moderate, PP2, PP3, PM2_Supporting, PM5_Supporting.
Met criteria codes
PM2_Supporting
This variant has an incomputable gnomAD v2.1.1 Popmax filtering allele frequency due to 1 copy in the European non-Finnish subpopulation and 0 copies in any other subpopulation, thereby meeting the ClinGen MDEP threshold criteria for PM2_Supporting (ENF Popmax FAF <= 0.000003 and <= 2 copies in ENF and <=1 copy in any other subpopulation) (PM2_Supporting).
PS4_Moderate
This variant was identified in 4 unrelated individuals with hyperglycemia (PS4; PMIDs: 34746319, 36257325).
PP2
GCK is defined by the ClinGen MDEP as a gene that has a low rate of benign missense variation and has pathogenic missense variants as a common mechanism of disease (PP2).
PP3
This variant is predicted to be deleterious by computational evidence, with a REVEL score of 0.916, which is greater than the MDEP VCEP threshold of 0.70 (PP3).
PM5_Supporting
Another missense variant, c.1361C>A p.Ala454Glu, has been classified as likely pathogenic by the ClinGen MDEP (PM5_Supporting).
Not Met criteria codes
PM1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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