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.1037C>T (p.Pro346Leu)

Curation Version - 1.2
Curation History
JSON LD for Version 1.2

CA270166553

225920 (ClinVar)

Gene: GATM

Condition: AGAT deficiency

Inheritance Mode: Autosomal recessive inheritance

Link to MONDO

UUID: d6b849b7-fb7c-480f-9d4f-b38631b90e9a

Approved on: 2025-04-11

Published on: 2025-04-11

HGVS expressions

NM_001482.3:c.1037C>T

NM_001482.3(GATM):c.1037C>T (p.Pro346Leu)

NC_000015.10:g.45364802G>A

CM000677.2:g.45364802G>A

NC_000015.9:g.45657000G>A

CM000677.1:g.45657000G>A

NC_000015.8:g.43444292G>A

NG_011674.1:g.18981C>T

NG_011674.2:g.42516C>T

ENST00000396659.8:c.1037C>T

ENST00000674905.1:c.1037C>T

ENST00000675158.1:c.1037C>T

ENST00000675323.1:c.1037C>T

ENST00000675701.1:c.977C>T

ENST00000675974.1:n.1128C>T

ENST00000676090.1:c.*1768C>T

ENST00000396659.7:c.1037C>T

ENST00000558336.5:c.1037C>T

ENST00000558362.5:n.2693C>T

ENST00000561376.1:n.84C>T

NM_001482.2:c.1037C>T

NM_001321015.1:c.650C>T

NM_001321015.2:c.650C>T

Uncertain Significance

BP4 PS3_Supporting PM2_Supporting

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.1037C>T variant in GATM is a missense variant predicted to cause substitution of proline by leucine at amino acid 346 (p.Pro346Leu). To our knowledge, this variant has not been reported in the literature in any individuals with AGAT deficiency. The highest population minor allele frequency in gnomAD v4.1.0. is 0.000002545 (3/1178764 alleles) in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). Expression of the variant in HeLa cells resulted in <10% wild type AGAT activity indicating that this variant may impact protein function (PMID 27233232)(PS3_Supporting). The computational predictor REVEL gives a score of 0.237 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (PMID: 36413997), and SpliceAI predicts that the variant has no impact on splicing (BP4). In summary, this variant meets the criteria to be classified as uncertain significance 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 2.0.0): PM2_Supporting, PS3_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on April 11, 2025).

BP4

The computational predictor REVEL gives a score of 0.237 which is below the threshold of 0.29, evidence that does not predict a damaging effect on AGAT function (PMID: 36413997)(BP4).

PS3_Supporting

The c.1037C>T (p.Pro346Leu) variant in GATM has been previously reported (PMID: 27233232): it was noted as a single heterozygous variant in one control individual, and follow-up functional assays (site-directed mutagenesis in HeLa cells) demonstrated that it resulted in <10% of wild-type enzyme activity (PS3). The authors of this report have deposited it in ClinVar (variant ID 225920) and stated that these results support its “putative pathogenicity.”

Functional analysis of GATM enzymatic activity of the p.Pro346Leu variant expressed in HeLa cells demonstrates <10% WT activity (PMID: 27233232). PubMed:27233232

PM2_Supporting

The highest population minor allele frequency in gnomAD v4.1.0. is 0.000002545 (3/1178764 alleles) in the non-Finnish European population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting).

Curation History

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