Submissions for variant NM_000277.3(PAH):c.833C>A (p.Thr278Asn)

dbSNP: rs62507262

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000665406	SCV002540169	pathogenic	Phenylketonuria	2020-10-29	reviewed by expert panel	curation	The c.833C>A (p.Thr278Asn) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded; PMID: 23764561, 16198137). This variant was detected with multiple pathogenic variants: p.R408W (PMID: 23764561); p.P281L (2 patients), and c.1315+1G>A (PMID: 23430918). This variant is absent in population databases Computational prediction tools and conservation analysis support a deleterious effect. Another missense change at the same amino acid (p.Thr278Ile) is pathogenic by 2 submitters. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3.
Counsyl	RCV000665406	SCV000789524	likely pathogenic	Phenylketonuria	2017-02-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000665406	SCV001361333	pathogenic	Phenylketonuria	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: PAH c.833C>A (p.Thr278Asn) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain (IPR041912) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251320 control chromosomes (gnomAD). c.833C>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Guldberg_1993, Fiori_2005, Sarkissian_2011, Polak_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000665406	SCV002246684	pathogenic	Phenylketonuria	2022-09-27	criteria provided, single submitter	clinical testing	This variant disrupts the p.Thr278 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9860305, 15503242, 18985011, 23271928). 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 expected to disrupt PAH protein function. ClinVar contains an entry for this variant (Variation ID: 102862). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 16198137, 23764561, 24705691). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 278 of the PAH protein (p.Thr278Asn). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000665406	SCV004209680	pathogenic	Phenylketonuria	2024-02-06	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089123	SCV000119731	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000665406	SCV002088642	pathogenic	Phenylketonuria	2021-03-16	no assertion criteria provided	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV000665406	SCV003927811	pathogenic	Phenylketonuria	2023-04-01	no assertion criteria provided	clinical testing