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_001482.3(GATM):c.608A>C (p.Tyr203Ser)

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CA263244

55921 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: a81a1862-e00b-4f6d-9452-bae1be767e3d

Approved on: 2025-04-11

Published on: 2025-04-11

HGVS expressions

NM_001482.3:c.608A>C

NM_001482.3(GATM):c.608A>C (p.Tyr203Ser)

NC_000015.10:g.45368137T>G

CM000677.2:g.45368137T>G

NC_000015.9:g.45660335T>G

CM000677.1:g.45660335T>G

NC_000015.8:g.43447627T>G

NG_011674.1:g.15646A>C

NG_011674.2:g.39181A>C

ENST00000396659.8:c.608A>C

ENST00000674905.1:c.608A>C

ENST00000675158.1:c.608A>C

ENST00000675323.1:c.608A>C

ENST00000675701.1:c.548A>C

ENST00000675974.1:n.699A>C

ENST00000676090.1:c.*1339A>C

ENST00000396659.7:c.608A>C

ENST00000558163.1:c.389A>C

ENST00000558336.5:c.608A>C

ENST00000558362.5:n.2264A>C

ENST00000558916.1:n.506A>C

NM_001482.2:c.608A>C

NM_001321015.1:c.221A>C

NM_001321015.2:c.221A>C

Likely Pathogenic

PS3_Supporting PP4_Strong PM2_Supporting PM3_Supporting

PP3 BP4

Evidence Links 0

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.608A>C variant in GATM is a missense variant that is predicted to result in substitution of tyrosine by serine at amino acid 203 (p.Tyr203Ser). This variant has been previously reported in two siblings (PMID: 23770102), both of whom showed significantly decreased creatine peak on H1-MRS and low GAA in plasma and low creatine in plasma (PP4_Strong). Both siblings were homozygous for the variant and their parents, who were first cousins, were confirmed to be heterozygous (PM3_Supporting). The variant is absent in gnomAD v4.1.0. (PM2_Supporting). When expressed in HeLa cells, the variant had 0% of wild-type GATM activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.64 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: 55921). In summary, this variant meets the criteria to be classified as likely pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes 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).

PS3_Supporting

The c.608A>C (p.Tyr203Ser) variant was found to have 0% of wild-type GATM activity when expressed in HeLa cells (PMID: 27233232) (PS3_Supporting).

PP4_Strong

The c.608A>C (p.Tyr203Ser) variant has been reported in two siblings, both of whom showed significantly decreased creatine peak on H1-MRS and low GAA in plasma and low creatine in plasma, features which are specific for AGAT deficiency (PP4_Strong).

PM2_Supporting

The variant is absent in gnomAD v4.1.0. (PM2_Supporting).

PM3_Supporting

The c.608A>C (p.Tyr203Ser) variant in GATM has been previously reported in two siblings who were homozygous for the variant; the parents, who were first cousins, were confirmed to be heterozygous for the variant (PMID: 23770102) (0.5 points) (PM3_Supporting).

PP3

The computational predictor REVEL gives a score of 0.64 which is neither above nor below the thresholds predicting a damaging (>0.644) or benign (<0.29) impact on AGAT function.

BP4

The computational predictor REVEL gives a score of 0.64 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.

Curation History

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