Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000810805 | SCV002540149 | likely pathogenic | Phenylketonuria | 2022-02-25 | reviewed by expert panel | curation | The c.794G>A (p.Cys265Tyr) variant in PAH is reported in a Japanese patient with phenylketonuria (BH4 deficiency excluded, PMID: 9860305). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. PAH activity in COS cell expression system was 0% (PMID: 9860305). In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PM2, PS3_supporting, PP3. |
Invitae | RCV000810805 | SCV000951039 | likely pathogenic | Phenylketonuria | 2018-07-23 | criteria provided, single submitter | clinical testing | This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with phenylketonuria (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 102836). This sequence change replaces cysteine with tyrosine at codon 265 of the PAH protein (p.Cys265Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (ExAC no frequency). Experimental studies have shown that this missense change abrogates PAH enzyme activity (PMID: 9860305). 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. |
De |
RCV000089095 | SCV000119702 | not provided | not provided | no assertion provided | not provided |