Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV000645719 | SCV003852697 | uncertain significance | Arginine:glycine amidinotransferase deficiency | 2023-01-24 | reviewed by expert panel | curation | The NM_001482.3:c.845G>A variant in GATM is a missense variant that is predicted to result in the substitution of arginine by histidine at amino acid 282 (p.Arg282His). To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00003 (1/34578 alleles) in the Latino population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% of wild-type GATM enzyme activity (PMID: 27233232) (PS3_Supporting). The computational predictor REVEL gives a score of 0.382 which is neither above nor below the thresholds predicting a damaging (>0.75) or benign (<0.15) impact on AGAT function. There is a ClinVar entry for this variant (Variation ID: 225918). 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. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023). |
| Invitae | RCV000645719 | SCV000767471 | uncertain significance | Arginine:glycine amidinotransferase deficiency | 2022-08-07 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 282 of the GATM protein (p.Arg282His). This variant is present in population databases (rs371447931, gnomAD 0.003%). This missense change has been observed in individual(s) with Arginine–glycine amidinotransferase (GATM) deficiency (PMID: 27233232). ClinVar contains an entry for this variant (Variation ID: 225918). 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: "Probably Damaging"; 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. |
| Ambry Genetics | RCV002444845 | SCV002680774 | uncertain significance | Inborn genetic diseases | 2017-07-12 | criteria provided, single submitter | clinical testing | The p.R282H variant (also known as c.845G>A), located in coding exon 6 of the GATM gene, results from a G to A substitution at nucleotide position 845. The arginine at codon 282 is replaced by histidine, an amino acid with highly similar properties. In one study, authors measured GATM activity of this alteration using liquid chromatography tandem mass spectrometry (LC-MS-MS) and showed that it retained <10% of wild-type GATM activity (DesRoches CL et al. Hum. Mutat., 2016 Sep;37:926-32).This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Fulgent Genetics, |
RCV002494553 | SCV002784132 | uncertain significance | Arginine:glycine amidinotransferase deficiency; Fanconi renotubular syndrome 1 | 2021-09-01 | criteria provided, single submitter | clinical testing | |
| Hospital for Sick Children | RCV000488910 | SCV000267669 | not provided | not provided | no assertion provided | in vitro |