Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001879840 | SCV002267206 | likely pathogenic | Cerebral creatine deficiency syndrome | 2021-08-26 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals affected with GAMT-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 3 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). ClinVar contains an entry for this variant (Variation ID: 975394). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV002222687 | SCV002500457 | likely pathogenic | Deficiency of guanidinoacetate methyltransferase | 2022-03-01 | criteria provided, single submitter | clinical testing | Variant summary: GAMT c.392-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250850 control chromosomes (gnomAD). To our knowledge, no occurrence of c.392-2A>G in individuals affected with Cerebral Creatine Deficiency Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Centre de Biologie Pathologie Génétique, |
RCV001251993 | SCV001427739 | likely benign | Intellectual disability | 2019-01-01 | no assertion criteria provided | clinical testing |