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.541G>A (p.Glu181Lys)

CA7542902

225914 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 3302c421-bff9-4f6e-af92-97d6e899f7e6
Approved on: 2025-04-11
Published on: 2025-04-11

HGVS expressions

NM_001482.3:c.541G>A
NM_001482.3(GATM):c.541G>A (p.Glu181Lys)
NC_000015.10:g.45368204C>T
CM000677.2:g.45368204C>T
NC_000015.9:g.45660402C>T
CM000677.1:g.45660402C>T
NC_000015.8:g.43447694C>T
NG_011674.1:g.15579G>A
NG_011674.2:g.39114G>A
ENST00000396659.8:c.541G>A
ENST00000674905.1:c.541G>A
ENST00000675158.1:c.541G>A
ENST00000675323.1:c.541G>A
ENST00000675701.1:c.481G>A
ENST00000675974.1:n.632G>A
ENST00000676090.1:c.*1272G>A
ENST00000396659.7:c.541G>A
ENST00000558163.1:c.322G>A
ENST00000558336.5:c.541G>A
ENST00000558362.5:n.2197G>A
ENST00000558916.1:n.439G>A
NM_001482.2:c.541G>A
NM_001321015.1:c.154G>A
NM_001321015.2:c.154G>A
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Uncertain Significance

Met criteria codes 2
PS3_Supporting PM2_Supporting
Not Met criteria codes 2
BP4 PP3

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.541G>A variant in GATM is a missense variant that is predicted to result in the substitution of glutamine by lysine at amino acid 181 (p.Glu181Lys). The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.00001864 (22/1180012 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% wild-type enzyme activity (PMID: 27233232). The computational predictor REVEL gives a score of 0.608, which neither predicts a damaging nor a benign impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. There is a ClinVar entry for this variant (Variation ID: 225914). 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. (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 <15% wild-type enzyme activity (PMID: 27233232).
When overexpressed in HeLa cells, the variant resulted in <15% wild-type enzyme activity. PubMed:27233232
PM2_Supporting
The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.00001864 (22/1180012 alleles) in the European non-Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting).
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.608, which neither predicts a damaging nor a benign impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing.
PP3
The computational predictor REVEL gives a score of 0.608, which neither predicts a damaging nor a benign inpact on AGAT function.
Curation History
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