Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001321015.2:c.166G>C

CA392261143

1478699 (ClinVar)

Gene: GATM (HGNC:2628)

Condition: AGAT deficiency (MONDO:0012996)

Inheritance Mode: Autosomal recessive inheritance

UUID: 34e85701-31a5-45f8-8d77-23cb3e6b7e82

Approved on: 2025-04-11

Published on: 2025-04-11

HGVS expressions

NM_001321015.2:c.166G>C

NC_000015.10:g.45368192C>G

CM000677.2:g.45368192C>G

NC_000015.9:g.45660390C>G

CM000677.1:g.45660390C>G

NC_000015.8:g.43447682C>G

NG_011674.1:g.15591G>C

NG_011674.2:g.39126G>C

ENST00000396659.8:c.553G>C

ENST00000674905.1:c.553G>C

ENST00000675158.1:c.553G>C

ENST00000675323.1:c.553G>C

ENST00000675701.1:c.493G>C

ENST00000675974.1:n.644G>C

ENST00000676090.1:c.*1284G>C

ENST00000396659.7:c.553G>C

ENST00000558163.1:c.334G>C

ENST00000558336.5:c.553G>C

ENST00000558362.5:n.2209G>C

ENST00000558916.1:n.451G>C

NM_001482.2:c.553G>C

NM_001321015.1:c.166G>C

NM_001482.3:c.553G>C

Likely Pathogenic

PM2_Supporting PS3_Supporting PP4_Strong PM3_Supporting

BP4 PP3

Evidence Links 1

Expert Panel

Cerebral Creatine Deficiency Syndromes VCEP

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.553G>C variant in GATM is a missense variant that is predicted to result in the substitution of alanine by proline at amino acid 185 (p.Ala185Pro). One patient, with one episode of seizure, myopathy, intellectual disability, and abnormal EMG, has been reported with absent creatine on brain MRS, as well as low urine guanidinoacetate, and low plasma guanidinoacetate with low plasma creatine (PMID: 26490222) (PP4_Strong). This individual is homozygous for the variant (PM3_Supporting). The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001562 (1/64012 alleles) in the Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion. This allele is the only allele in gnomAD v4.1.0. (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% wild-type enzyme activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.528 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. In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 2.0.0): PP4_Strong, PS3_Supporting, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025).

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0 is 0.00001562 (1/64012 alleles) in the Finnish population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion. This allele is the only allele in gnomAD v4.1.0. (PM2_Supporting).

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 (PMID: 27233232). PubMed:27233232

PP4_Strong

One patient, with one episode of seizure, myopathy, intellectual disability, and abnormal EMG, had absent creatine on brain MRS, as well as low urine guanidinoacetate, and low plasma guanidinoacetate with low plasma creatine (PMID: 26490222) (PP4_Strong).

PM3_Supporting

PMID: 26490222: Found in a single patient who was homozygous for the variant (0.5pts)

BP4

The computational predictor REVEL gives a score of 0.528 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.

PP3

The computational predictor REVEL gives a score of 0.528 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function.

Curation History

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