Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV001553736 | SCV002600153 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2022-06-06 | reviewed by expert panel | curation | The NM_000156.6:c.316C>T variant in GAMT is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 2/6 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two patients with this variant have been reported with clinical features consistent with GAMT deficiency, elevated guanidinoacetate in urine or plasma, and low or absent creatine peak on brain magnetic resonance spectroscopy (MRS), and one of these patients also had evidence of a guanidinoacetate peak on brain MRS (PMID: 20049533, 24415674, 29506905) (PP4_Strong). Both patients (who have different descriptions) are compound heterozygous for the variant and c.407C>T (p.Thr136Met), phase unknown (PMID 20049533, 24415674, 29506905). The allelic data from these patients will be used in the assessment of p.Thr136Met and is not included here to avoid circular logic. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 566624). In summary, this variant meets the criteria to be classified as pathogenic for GAMT 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): PVS1, PP4_strong, PM2_supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). |
| Labcorp Genetics |
RCV000686487 | SCV000814007 | pathogenic | Cerebral creatine deficiency syndrome | 2023-09-06 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Gln106*) in the GAMT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GAMT are known to be pathogenic (PMID: 15108290). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with cerebral creatine deficiency syndrome (PMID: 21140503). ClinVar contains an entry for this variant (Variation ID: 566624). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. |
| Mendelics | RCV000986200 | SCV001135123 | pathogenic | not provided | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Kariminejad - |
RCV001814217 | SCV001755309 | pathogenic | Abnormality of the nervous system | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001553736 | SCV001774721 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2021-07-23 | criteria provided, single submitter | clinical testing | Variant summary: GAMT c.316C>T (p.Gln106X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 181168 control chromosomes (gnomAD). c.316C>T has been reported in the literature in individuals (in compound heterozygous state) affected with Guanidinoactetate Methyltransferase Deficiency (example: Alcaide_2011, Khaikin_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Alcaide_2011). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Baylor Genetics | RCV001553736 | SCV004198594 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2024-01-16 | criteria provided, single submitter | clinical testing |