Submissions for variant NM_000277.3(PAH):c.1240T>C (p.Tyr414His)

dbSNP: rs281865437

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106346	SCV001250536	uncertain significance	Phenylketonuria	2019-05-05	reviewed by expert panel	curation	The c.1240T>C (p.Tyr414His) variant in PAH has been previously reported Likely Pathogenic by one clinical laboratory in ClinVar (see variant ID 125859); the collection method is stated as "literature only" and no further information is provided. To our knowledge, as of 4/29/19, it has not been reported in the published literature. The variant results in the substitution of a highly conserved Tyrosine residue with Histidine, a physiochemically distinct amino acid (nonpolar versus basic side chains), and the amino acid substitution is predicted damaging by multiple lines of computational evidence e.g., Predicted deleterious in SIFT, Polyphen2, Mutation Taster. REVEL= 0.969) (PP3). It is present at extremely low frequency in control databases including ethnically matched individuals, including gnomAD/ExAC, 1000 Genomes, and ESP: the highest MAF reported is 0.00001, in the gnomAD/ExAC Non-Finnish European subpopulation, which falls below the 0.0002 allele frequency cutoff for PAH variants (PM2). Another missense variant at this site, p.Tyr414Cys, has been previously reported Pathogenic, including by the ClinGen PAH working group (see ClinVar variant ID 593) (PM5).
Invitae	RCV000106346	SCV002216693	pathogenic	Phenylketonuria	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 414 of the PAH protein (p.Tyr414His). This variant is present in population databases (rs281865437, gnomAD 0.0009%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 120265). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. This variant disrupts the p.Tyr414 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8556304, 9399896, 10479481, 24296287). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Inserm U 954, Faculté de Médecine de Nancy	RCV000106346	SCV000143845	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.