Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001778707 | SCV002818503 | likely pathogenic | Phenylketonuria | 2022-12-09 | reviewed by expert panel | curation | The c.535T>C (p.Tyr179His) variant in PAH has been reported in multiple individuals with PKU, including in patients with classic PKU in whom BH4 deficiency has been excluded (PMID: 29997390, PMID: 16256386, PMID: 20920871, PMID: 32668217, PMID: 30389586). p.Tyr179His has been detected with multiple variants classified as likely pathogenic or pathogenic by PAH VCEP, including p.Arg176*, c.1066-11G>A, c.1199+1G>C, p.Ala403Val, p.Ile406Met, p.Arg408Trp, p.Val230Ile (PMID: 32668217). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_Strong, PM2, PP4_Moderate, PP3. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001778707 | SCV002014805 | pathogenic | Phenylketonuria | 2021-10-08 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.535T>C (p.Tyr179His) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251232 control chromosomes (gnomAD). c.535T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (e.g. Song_2006, Zare-Karizi_2011, Sarkissian_2012, Shirzadeh_2018). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
De |
RCV000088979 | SCV000119583 | not provided | not provided | no assertion provided | not provided |