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
More

Benign

Met criteria codes 2
BA1 BS3_Supporting
Not Met criteria codes 2
PP3 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 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
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).
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
Not Met criteria codes
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.
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.
Curation History
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