Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV003482159 | SCV004227924 | pathogenic | Deficiency of guanidinoacetate methyltransferase | 2023-12-14 | reviewed by expert panel | curation | The NM_000156.6:c.328-2A>G variant in GAMT occurs within the canonical splice acceptor site of intron 2. It is predicted to cause skipping of the biologically relevant exon 3/6, resulting in a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant meets PM2_Supporting using the gnomAD v4 dataset. An individual with clinical symptoms consistent with GAMT deficiency, including increased GAA levels in blood and a decreased brain creatine peak via MRS, was reported who was compound heterozygous for this variant and another GAMT variant, c.115A>G (PMID:37305710) (PP4_Strong). PM3 was not applied to the compound heterozygote (c.328-2A>G; c.115A>G(p.Lys39Glu)) in PMID37305710 as the allelic data from this patient will be used in the assessment of c.115A>G(p.Lys39Glu) and is not included here to avoid circular logic. There is a ClinVar entry for this variant (Variation ID: 854099). In summary, this variant meets the criteria to be classified as Pathogenic for GAMT deficiency as specified by the ClinGen CCDS Variant Curation Expert Panel (Specifications Version 1.1.0), PM2_Supporting, PVS1, PP4_Strong. (Classification approved by the ClinGen CCDS VCEP on December 14, 2023) |
Invitae | RCV001059066 | SCV001223671 | likely pathogenic | Cerebral creatine deficiency syndrome | 2023-11-02 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 2 of the GAMT gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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 variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 854099). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |