Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001069317 | SCV002032199 | pathogenic | Phenylketonuria | 2020-08-10 | reviewed by expert panel | curation | The c.1200-2A>G variant in PAH is a null variant (canonical - 2 splice site); Loss of function is a known mechanism of disease, exon skipping disrupts reading frame and is predicted to undergo NMD (not located in last 50bp of preliminary exon). Coding exon 12/13 is present in biologically-relevant transcript. This variant has been reported in 2 individuals with PKU (BH4 deficiency excluded, PMID: 21147011, 24301756). This variant is absent in population databases. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PP4_Moderate. |
Invitae | RCV001069317 | SCV001234477 | pathogenic | Phenylketonuria | 2022-06-17 | criteria provided, single submitter | clinical testing | This variant is also known as IVS11-2A>G. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 862570). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 21890392, 24301756). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 11 of the PAH 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 PAH are known to be pathogenic (PMID: 1301187, 9634518). |
Natera, |
RCV001069317 | SCV002088620 | pathogenic | Phenylketonuria | 2020-08-13 | no assertion criteria provided | clinical testing |