ClinVar Miner

Submissions for variant NM_001482.3(GATM):c.985C>G (p.Leu329Val)

gnomAD frequency: 0.00001  dbSNP: rs373802463
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen RCV003159111 SCV003852683 uncertain significance Arginine:glycine amidinotransferase deficiency 2022-12-08 reviewed by expert panel curation The NM_001482.3:c.985C>G variant in GATM is a missense variant that is predicted to result in the substitution of leucine by valine at position 329 (p.Leu329Val). This variant was reported 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 (PMID: 27233232) (PS3_Supporting). The authors of this report have deposited it in ClinVar (variant ID 225919). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00002 (2/113682 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.04 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). 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 1.1.0): PS3_Supporting, PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCP on December 8, 2022).
Hospital for Sick Children RCV000488890 SCV000267670 not provided not provided no assertion provided in vitro

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