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 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.1244G>A (p.Arg415Gln)

CA7542752

225921 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 4f0d661f-348c-4946-ae2d-e3ce705a0584
Approved on: 2024-08-20
Published on: 2024-09-20

HGVS expressions

NM_001482.3:c.1244G>A
NM_001482.3(GATM):c.1244G>A (p.Arg415Gln)
NC_000015.10:g.45362137C>T
CM000677.2:g.45362137C>T
NC_000015.9:g.45654335C>T
CM000677.1:g.45654335C>T
NC_000015.8:g.43441627C>T
NG_011674.1:g.21646G>A
NG_011674.2:g.45181G>A
ENST00000396659.8:c.1244G>A
ENST00000674905.1:c.*206G>A
ENST00000675158.1:c.*144G>A
ENST00000675323.1:c.*1746G>A
ENST00000675701.1:c.1184G>A
ENST00000675974.1:n.3793G>A
ENST00000676090.1:c.*1975G>A
ENST00000396659.7:c.1244G>A
ENST00000558362.5:n.2900G>A
NM_001482.2:c.1244G>A
NM_001321015.1:c.857G>A
NM_001321015.2:c.857G>A
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Benign

Met criteria codes 2
BS3_Supporting BA1
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 1

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Cerebral Creatine Deficiency Syndromes VCEP
The NM_001482.3:c.1244G>A variant in GATM is a missense variant predicted to cause the substitution of an arginine by a glutamine at amino acid position 415 (p.Arg415Gln). The highest population minor allele frequency in gnomAD v2.1.1 is 0.000915 (28/30616 alleles) in the South Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). Expression of the variant in HeLa cells resulted in 39% wild type AGAT activity suggesting that this variant does not significantly impact protein function (PMID: 27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.201 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. There is a ClinVar entry for this variant (Variation ID: 225921). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BS3_Supporting. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024).
Met criteria codes
BS3_Supporting
Retains 39% of wild-type GATM activity when expressed in HeLa cells (DesRoches et al, 2016, PMID: 27233232)
p.Arg415Gln retains >30% of wild-type GATM enzymatic activity when expressed in HeLa cells. PubMed:27233232
BA1
The highest minor population allele frequency in gnomAD v2.1.1. is 0.00091 (28/30616) in the S. Asian population which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1).
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.201 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function.
PP3
The computational predictor REVEL gives a score of 0.201 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function.
Curation History
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