ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs142814307
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Total submissions: 3
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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 RCV002515607 SCV003852693 uncertain significance Arginine:glycine amidinotransferase deficiency 2023-01-24 reviewed by expert panel curation 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 v2.1.1 is 0.000009 (1/113704 alleles) in the non-Finnish European population, which is lower than the ClinGen LSD 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 neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. 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 1.1.0): PM2_Supporting, PS3_Supporting. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023).
Labcorp Genetics (formerly Invitae), Labcorp RCV002515607 SCV003442839 uncertain significance Arginine:glycine amidinotransferase deficiency 2022-08-31 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 346 of the GATM protein (p.Pro346Leu). This variant is present in population databases (rs142814307, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with GATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 225920). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GATM function (PMID: 27233232). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Hospital for Sick Children RCV000488898 SCV000267671 not provided not provided no assertion provided in vitro

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