Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001260324 | SCV004015303 | pathogenic | Phenylketonuria | 2023-03-16 | reviewed by expert panel | curation | The c.199T>C (p.Ser67Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; 8533759; 26351554). This variant has an extremely low allele frequency in ExAC (MAF=0.00002, PM2). This variant was detected in trans with L48S (PMID: 8592329), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP) PMID: 26351554 (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.954) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP4_Moderate, PP3. |
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000088867 | SCV000888346 | pathogenic | not provided | 2018-04-05 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001260324 | SCV001437249 | likely pathogenic | Phenylketonuria | 2020-09-21 | criteria provided, single submitter | clinical testing | Variant summary: PAH c.199T>C (p.Ser67Pro) results in a non-conservative amino acid change located in the ACT domain (IPR002912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251284 control chromosomes. c.199T>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) and has been subsequently cited by others (example, Daniele_2006, Bik-Multanowski_2013, Bagheri_2015). These data indicate that the variant is very likely to be associated with disease. However, to our knowledge, no concrete experimental evidence demonstrating an impact on protein function was ascertained in the context of this classification. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Labcorp Genetics |
RCV001260324 | SCV002246406 | pathogenic | Phenylketonuria | 2024-11-06 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 67 of the PAH protein (p.Ser67Pro). This variant is present in population databases (rs5030842, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12409276, 16198137, 19292873, 19913839). ClinVar contains an entry for this variant (Variation ID: 102625). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PAH protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
De |
RCV000088867 | SCV000119463 | not provided | not provided | no assertion provided | not provided |