Submissions for variant NM_000277.3(PAH):c.1301C>A (p.Ala434Asp)

dbSNP: rs199475659

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169393	SCV004222613	pathogenic	Phenylketonuria	2023-12-30	reviewed by expert panel	curation	The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID: 18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID: 16256386); p.E390G, p.R261Q (PMID: 21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID: 23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3.
Counsyl	RCV000169393	SCV000220785	likely pathogenic	Phenylketonuria	2014-10-13	criteria provided, single submitter	literature only
Invitae	RCV000169393	SCV001579238	pathogenic	Phenylketonuria	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 434 of the PAH protein (p.Ala434Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 16256386, 18247293, 24401910, 27264808, 29499199). ClinVar contains an entry for this variant (Variation ID: 102586). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 30037505). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169393	SCV004209615	pathogenic	Phenylketonuria	2023-08-21	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088825	SCV000119416	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169393	SCV002088616	pathogenic	Phenylketonuria	2021-07-29	no assertion criteria provided	clinical testing