Submissions for variant NM_000277.3(PAH):c.242C>A (p.Thr81Asn)

dbSNP: rs796064502

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000190376	SCV000886571	likely pathogenic	Phenylketonuria	2018-12-10	reviewed by expert panel	curation	The c.242C>A (p.Thr81Asn) variant in PAH is reported in 1 PKU patient. PAH and BH4DH genes were sequenced. It was detected with p.V230I which is interpreted as Pathogenic/Likely Pathogenic in ClinVar. (PMID: 23942198) This variant is absent from ExAC, gnomAD, 1000G, and ESP. A deleterious effect is predicted in SIFT, MutationTaster, and Polyphen-2. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4_Moderate, PM3, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000190376	SCV003441163	likely pathogenic	Phenylketonuria	2022-10-13	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 208180). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 81 of the PAH protein (p.Thr81Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hyperphenylalaninemia (PMID: 23942198; Invitae). 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. This variant disrupts the p.Thr81 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8659548, 23430918). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Inserm U 954, Faculté de Médecine de Nancy	RCV000190376	SCV000243910	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.