Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003298627 | SCV004009599 | likely pathogenic | Deficiency of guanidinoacetate methyltransferase | 2023-05-25 | reviewed by expert panel | curation | The NM_000156.6:c.526del (p.Glu176SerfsTer2) variant in GAMT is a frameshift variant predicted to cause a premature stop codon in the last 50 nucleotides of the penultimate exon/the last exon of the gene and therefore to escape nonsense mediated decay. More than 10% of the protein is predicted to be removed (PVS1_Strong). This variant in not in gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in one individual with GAMT deficiency who had elevated GAA and low creatine in plasma and in urine (PMID: 19288536) (PP4_Moderate). There is a ClinVar entry for this variant (Variation ID: 1067935, 1 star review status) with 1 submitter classifying the variant as likely pathogenic. In summary, this variant meets the criteria to be classified as likely 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_Strong, PM2_Supporting, PP4_Moderate. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on April 13, 2023) |
| Labcorp Genetics |
RCV001379333 | SCV001577119 | pathogenic | Cerebral creatine deficiency syndrome | 2023-08-04 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Glu176Serfs*2) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 61 amino acid(s) of the GAMT protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with guanidinoacetate methyltransferase (GAMT) deficiency (PMID: 19288536). ClinVar contains an entry for this variant (Variation ID: 1067935). This variant disrupts a region of the GAMT protein in which other variant(s) (p.Gln193*) have been determined to be pathogenic (PMID: 23234264, 31130284). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Baylor Genetics | RCV003298627 | SCV004198584 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2024-02-17 | criteria provided, single submitter | clinical testing |