Submissions for variant NM_000277.3(PAH):c.1220C>T (p.Pro407Leu)

dbSNP: rs62644473

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000667	SCV001572850	likely pathogenic	Phenylketonuria	2020-08-28	reviewed by expert panel	curation	The c.1220C>T (p.Pro407Leu) variant in PAH has been reported in multiple individuals with PAH deficiency (PMID: 9950317, 23357515, 23792259). This variant is absent in population databases. This variant was detected with pathogenic variants: p.F55fs (PMID: 9950317); p.Tyr414Cys (PMID: 23357515); p.Ala403Val (PMID: 23792259); and p.R408W (PMID: 24350308). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PM3_strong.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000667	SCV002245680	pathogenic	Phenylketonuria	2023-08-22	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 407 of the PAH protein (p.Pro407Leu). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro407 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9359039, 10484807, 14681498, 14726806, 15503242). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 635). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 9950317). 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).
OMIM	RCV000000667	SCV000020817	pathogenic	Phenylketonuria	1999-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088804	SCV000119393	not provided	not provided		no assertion provided	not provided