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.622G>A (p.Ala208Thr)

CA7542887

225916 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 4a9a1dbb-9011-450e-93e6-c4a0228b6f25
Approved on: 2025-04-11
Published on: 2025-04-11

HGVS expressions

NM_001482.3:c.622G>A
NM_001482.3(GATM):c.622G>A (p.Ala208Thr)
NC_000015.10:g.45368123C>T
CM000677.2:g.45368123C>T
NC_000015.9:g.45660321C>T
CM000677.1:g.45660321C>T
NC_000015.8:g.43447613C>T
NG_011674.1:g.15660G>A
NG_011674.2:g.39195G>A
ENST00000396659.8:c.622G>A
ENST00000674905.1:c.622G>A
ENST00000675158.1:c.622G>A
ENST00000675323.1:c.622G>A
ENST00000675701.1:c.562G>A
ENST00000675974.1:n.713G>A
ENST00000676090.1:c.*1353G>A
ENST00000396659.7:c.622G>A
ENST00000558163.1:c.403G>A
ENST00000558336.5:c.622G>A
ENST00000558362.5:n.2278G>A
ENST00000558916.1:n.520G>A
NM_001482.2:c.622G>A
NM_001321015.1:c.235G>A
NM_001321015.2:c.235G>A
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Uncertain Significance

Met criteria codes 2
PM2_Supporting PS3_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 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.622G>A variant in GATM is a missense variant that is predicted to result in the substitution of alanine by threonine at amino acid 208 (p.Ala208Thr). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.00002228 (1/44874 alleles) in the East Asian 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% of wild-type AGAT enzyme activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.48 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function. SpliceAI predicts that the variant has no impact on splicing. There is a ClinVar entry for this variant (Variation ID: 225916). 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
PM2_Supporting
The highest population minor allele frequency for this variant in gnomAD v4.1.0. is 0.00002228 (1/44874 alleles) in the East Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting).
PS3_Supporting
When overexpressed in HeLa cells, the variant resulted in <15% of wild-type AGAT enzyme activity (PMID: 27233232)
When overexpressed in HeLa cells, the variant resulted in <15% of wild-type AGAT enzyme activity. PubMed:27233232
Not Met criteria codes
PP3
The computational predictor REVEL gives a score of 0.48, evidence that neither predicts a damaging nor benign impact on AGAT function.
BP4
The computational predictor REVEL gives a score of 0.48, evidence that neither predicts a damaging nor benign impact on AGAT function.
Curation History
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