Submissions for variant NM_000277.3(PAH):c.1114A>T (p.Thr372Ser)

dbSNP: rs62517163

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000306209	SCV002032192	likely pathogenic	Phenylketonuria	2020-08-14	reviewed by expert panel	curation	The c.1114A>T (p.Thr372Ser) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded, PMID: 8807319, 21147011, 30050108). This variant has an extremely low frequency in gnomAD (MAF=0.00001). This variant was detected with multiple pathogenic/likely pathogenic variants: p.R408W, c.1066-11G>A (PMID: 21147011); p.A300S (PMID: 8807319); p.P281L (2 patients, LP), delF39 (PMID: 10947211). 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_Moderate, PM2, PM3_strong.
Illumina Laboratory Services, Illumina	RCV000306209	SCV000375563	likely pathogenic	Phenylketonuria	2017-04-28	criteria provided, single submitter	clinical testing	The PAH c.1114A>T (p.Thr372Ser) missense variant has been reported in three studies in which it is found in a total of six Turkish patients with hyperphenylalanemia, a milder form of phenylalanine hydroxylase deficiency, in a compound heterozygous state (van der Sijs-Bos et al. 1996; Yilmaz et al. 2000; Ãœnal et al. 2015). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project or the Exome Aggregation Consortium. Based on the evidence, the p.Thr372Ser variant is classified as likely pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Fulgent Genetics, Fulgent Genetics	RCV000306209	SCV002810349	pathogenic	Phenylketonuria	2022-05-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000306209	SCV004294265	pathogenic	Phenylketonuria	2022-11-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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: 102528). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 8807319, 30747360, 32668217; BIOPKU http://www.biopku.org). This variant is present in population databases (rs62517163, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 372 of the PAH protein (p.Thr372Ser).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088761	SCV000119345	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000306209	SCV000793301	likely pathogenic	Phenylketonuria	2017-08-10	no assertion criteria provided	clinical testing