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 | 2022-11-24 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1402763). This variant is also known as p.A22fsX19. This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (PMID: 15108290, 27650626). 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 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). |
| Baylor Genetics | RCV003159217 | SCV004198599 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2023-03-25 | criteria provided, single submitter | clinical testing |