Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV001388783 | SCV001762301 | likely pathogenic | Phenylketonuria | 2021-05-29 | reviewed by expert panel | curation | The c.1262T>C (p.Ile421Thr) variant in PAH has been reported in multiple individuals with mild and classic PKU (BH4 deficiency excluded) (PMID: 26503515, PMID: 27121329, PMID: 23514811). This variant has low frequency (MAF=0.00001) in gnomAD. This variant was detected with pathogenic variants: R241H (PMID: 27121329); p.Arg408Gln (PMID: 25456745); IVS5-1G>A, p.Val399= (PMID: 29316886); Ex9_11del (LP PAH VCEP) PMID: 31623983. Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_vstrong, PP3. |
Invitae | RCV001388783 | SCV001589915 | pathogenic | Phenylketonuria | 2023-12-05 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 421 of the PAH protein (p.Ile421Thr). This variant is present in population databases (rs199475696, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 27121329, 30050108, 31355225). ClinVar contains an entry for this variant (Variation ID: 102582). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
Baylor Genetics | RCV001388783 | SCV004209660 | pathogenic | Phenylketonuria | 2023-06-03 | criteria provided, single submitter | clinical testing | |
De |
RCV000088820 | SCV000119411 | not provided | not provided | no assertion provided | not provided |