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.565C>T (p.Arg189Cys)

CA7542898

225915 (ClinVar)

Gene: GATM
Condition: AGAT deficiency
Inheritance Mode: Autosomal recessive inheritance
Link to MONDO
UUID: 3922b100-047f-4637-b91f-394c286c2cba
Approved on: 2025-04-11
Published on: 2025-04-11

HGVS expressions

NM_001482.3:c.565C>T
NM_001482.3(GATM):c.565C>T (p.Arg189Cys)
NC_000015.10:g.45368180G>A
CM000677.2:g.45368180G>A
NC_000015.9:g.45660378G>A
CM000677.1:g.45660378G>A
NC_000015.8:g.43447670G>A
NG_011674.1:g.15603C>T
NG_011674.2:g.39138C>T
ENST00000396659.8:c.565C>T
ENST00000674905.1:c.565C>T
ENST00000675158.1:c.565C>T
ENST00000675323.1:c.565C>T
ENST00000675701.1:c.505C>T
ENST00000675974.1:n.656C>T
ENST00000676090.1:c.*1296C>T
ENST00000396659.7:c.565C>T
ENST00000558163.1:c.346C>T
ENST00000558336.5:c.565C>T
ENST00000558362.5:n.2221C>T
ENST00000558916.1:n.463C>T
NM_001482.2:c.565C>T
NM_001321015.1:c.178C>T
NM_001321015.2:c.178C>T
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Uncertain Significance

Met criteria codes 2
PS3_Supporting PP3_Moderate
Not Met criteria codes 2
BS1 PM2

Evidence Links 0

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.565C>T variant in GATM is a missense variant that is predicted to result in the substitution of arginine by cysteine at amino acid 189 (p.Arg189Cys). To our knowledge, this variant has not been reported in individuals with AGAT deficiency in the published literature. The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006683 (3/44888 alleles) in the East Asian population. This is higher than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), and lower than the threshold for BS1 (Grpmax >0.0001). Therefore, none of the population data codes are met. When overexpressed in HeLa cells, the variant resulted in <10% of wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of [0.881] which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate). There is a ClinVar entry for this variant (Variation ID: 225915). 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, PP3_Moderate. (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 <10% of wild-type enzyme activity (PMID: 27233232).
PP3_Moderate
The computational predictor REVEL gives a score of [0.881] which is above the threshold of 0.773, evidence that correlates with impact to IDUA function at the moderate level based on the specifications of the ClinGen Lysosomal Diseases VCEP (PMID: 36413997) (PP3_Moderate).
Not Met criteria codes
BS1
The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006683 (3/44888 alleles) in the East Asian population. This is higher than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), and lower than the threshold for BS1 (Grpmax >0.0001). Therefore, none of the population data codes are met.
PM2
The highest population minor allele frequency in gnomAD v4.1.0. is 0.00006683 (3/44888 alleles) in the East Asian population. This is higher than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), and lower than the threshold for BS1 (Grpmax >0.0001). Therefore, none of the population data codes are met.
Curation History
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