Submissions for variant NM_000277.3(PAH):c.155T>C (p.Leu52Ser)

dbSNP: rs199475630

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001389300	SCV002540151	likely pathogenic	Phenylketonuria	2022-03-05	reviewed by expert panel	curation	The c.155T>C (p.Leu52Ser) variant in PAH is reported in 2 patients with PAH deficiency, detected with pathogenic variants: Exon 5_6 deletion and p.R243Q (BH4 deficiency excluded, PMID: 15319459, 30050108). PAH activity in COS cells was 27% (PMID: 9860305). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets the criteria to be classified as Likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH VCEP: PP4_moderate, PM2, PM3, PS3_supporting, PP3.
Invitae	RCV001389300	SCV001590613	pathogenic	Phenylketonuria	2020-08-05	criteria provided, single submitter	clinical testing	Experimental studies have shown that this variant affects PAH protein function or expression (PMID: 9860305). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu52 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 31102715), which suggests that this may be a clinically significant amino acid residue. 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. This variant has been observed in individual(s) with phenylalanine hydroxylase deficiency (PMID: 21307867, 26503515). ClinVar contains an entry for this variant (Variation ID: 102599). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with serine at codon 52 of the PAH protein (p.Leu52Ser). The leucine residue is highly conserved and there is a large physicochemical difference between leucine and serine.
Baylor Genetics	RCV001389300	SCV004209629	likely pathogenic	Phenylketonuria	2023-07-28	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088840	SCV000119433	not provided	not provided		no assertion provided	not provided