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]
  • Gene label mismatch: GATM vs undefined
  • 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!

Variant: NM_001482.3(GATM):c.314C>T (p.Pro105Leu)

CA270169359

225913 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 7b82d38c-52aa-4157-a3e1-b8f1eaeb6282
Approved on: 2025-04-11
Published on: 2025-04-11

HGVS expressions

NM_001482.3:c.314C>T
NM_001482.3(GATM):c.314C>T (p.Pro105Leu)
NC_000015.10:g.45369496G>A
CM000677.2:g.45369496G>A
NC_000015.9:g.45661694G>A
CM000677.1:g.45661694G>A
NC_000015.8:g.43448986G>A
NG_011674.1:g.14287C>T
NG_011674.2:g.37822C>T
ENST00000396659.8:c.314C>T
ENST00000674905.1:c.314C>T
ENST00000675158.1:c.314C>T
ENST00000675323.1:c.314C>T
ENST00000675701.1:c.254C>T
ENST00000675974.1:n.405C>T
ENST00000676090.1:c.*1045C>T
ENST00000396659.7:c.314C>T
ENST00000558118.1:c.*119C>T
ENST00000558163.1:c.95C>T
ENST00000558336.5:c.314C>T
ENST00000558362.5:n.1970C>T
ENST00000558537.5:c.-74C>T
ENST00000558916.1:n.212C>T
ENST00000559885.1:c.-74C>T
ENST00000561148.5:c.-74C>T
NM_001482.2:c.314C>T
NM_001321015.1:c.-74C>T
NM_001321015.2:c.-74C>T
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Uncertain Significance

Met criteria codes 3
PS3_Supporting PM2_Supporting BP4

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Cerebral Creatine Deficiency Syndromes Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for GATM Version 2.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cerebral Creatine Deficiency Syndromes VCEP
The NM_001482.3:c.314C>T variant in GATM is a missense variant that is predicted to result in the substitution of proline by leucine and amino acid position 105 (p.Pro105Leu). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. It is absent in gnomAD v4.1.0. (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in 0.6% wild-type activity (PMID: 27233232; ClinVar Variation ID: 225913 - see Germline Functional Evidence section) which is below the threshold of the CCDS VCEP of <15% wild-type activity, indicating the the variant may impact the function of the protein (PS3_Supporting). The computational predictor REVEL gives a score of 0.066 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 225913). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PS3_Supporting, PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025).
Met criteria codes
PS3_Supporting
When overexpressed in HeLa cells, the variant resulted in 0.6% wild-type activity (PMID: 27233232; ClinVar Variation ID: 225913 - see Germline Functional Evidence section) which is below the threshold of the CCDS VCEP of <15% wild-type activity, indicating the the variant may impact the function of the protein.
When overexpressed in HeLa cells, the variant resulted in <15% of wild-type activity. PubMed:27233232
PM2_Supporting
Absent in gnomAD v4.1.0. (PM2_Supporting).
BP4
The computational predictor REVEL gives a score of 0.066 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (BP4).
Curation History
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