Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001833117 | SCV002600163 | uncertain significance | Deficiency of guanidinoacetate methyltransferase | 2022-06-06 | reviewed by expert panel | curation | The NM_000156.6:c.689C>T variant in GAMT is a missense variant in exon 6, predicted to result in the substitution of threonine for methionine at amino acid 230 (p.Thr230Met). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001308 (4/ 30576) in the South Asian population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.0004), meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.48 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAMT function (BP4). To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency, and the results of functional studies are unavailable. This variant has been previously reported in ClinVar (Variation ID: 205595). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). |
| Gene |
RCV000187580 | SCV000241174 | uncertain significance | not provided | 2014-03-06 | criteria provided, single submitter | clinical testing | p.Thr230Met (ACG>ATG): c.689 C>T in exon 6 of the GAMT gene (NM_000156.4) The T230M variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T230M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge, nearby missense mutations in the GAMT gene have not been reported in individuals with GAMT-related disorders. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s). |
| Labcorp Genetics |
RCV000814698 | SCV000955117 | uncertain significance | Cerebral creatine deficiency syndrome | 2022-08-23 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 230 of the GAMT protein (p.Thr230Met). This variant is present in population databases (rs776537906, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 205595). 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"). 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. |
| Natera, |
RCV001833117 | SCV002087002 | uncertain significance | Deficiency of guanidinoacetate methyltransferase | 2019-10-28 | no assertion criteria provided | clinical testing |