Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003159217 | SCV003852708 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2023-03-09 | reviewed by expert panel | curation | The NM_000156.6:c.64dup (p.Ala22GlyfsTer63) variant in GAMT is a frameshift variant predicted to cause a premature stop codon, leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). Two affected unrelated individuals, previously reported (PMID: 27650626, PMID: 15108290), were homozygous for the variant; one of these individuals (PMID: 15108290) had elevated urinary guanidinoacetate and absent GAMT enzyme activity in fibroblasts with full GAMT gene sequencing performed, and the other proband (PMID: 27650626) had low serum and urine creatinine and absent creatine peak on brain MRS. (PM3, PP4_Strong), This variant is absent from population databases (PM2_Supporting). This variant has also been reported in ClinVar (Variation ID: 1402763). In summary, this variant meets criteria to be classified as pathogenic for guanidinoacetate methyltransferase deficiency. GAMT-specific ACMG/AMP criteria applied (Specifications Version 1.1.0): PVS1, PP4_Strong, PM2_Supporting, PM3, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on March 9, 2023) |
| Labcorp Genetics |
RCV001908704 | SCV002168859 | pathogenic | Cerebral creatine deficiency syndrome | 2024-02-04 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Ala22Glyfs*63) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (PMID: 15108290, 27650626). This variant is also known as p.A22fsX19. ClinVar contains an entry for this variant (Variation ID: 1402763). For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV003159217 | SCV004198599 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2023-03-25 | criteria provided, single submitter | clinical testing |