Submissions for variant NM_000277.3(PAH):c.818C>T (p.Ser273Phe)

gnomAD frequency: 0.00001  dbSNP: rs62514953

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000629	SCV000852145	likely pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC and gnomAD (1 allele); PP3: Deleterious effect predicted in SIFT, Polyphen2, MutationTaster. REVEL=0.978; PP4_Moderate: S273F was detected in in Northern Ireland, Belgium/French, Western Scotland, and New South Wales PKU patients. BH4 deficiency was assessed in 1 study. Upgraded per ClinGen Metabolic workgroup. (PMID:1671881; PMID:8533759; PMID:9012412; PMID:24368688); PM3_Strong: Seen with 2 known pathogenic mutations: I65T, R408W. Upgraded based on SVI worgroup recommendations and approved PAH guidelines (PMID:24368688). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3_Strong).
Baylor Genetics	RCV000000629	SCV001163719	pathogenic	Phenylketonuria	2024-03-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000629	SCV001230923	pathogenic	Phenylketonuria	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 273 of the PAH protein (p.Ser273Phe). This variant is present in population databases (rs62514953, gnomAD 0.0009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 24368688; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 598). 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.Ser273 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 11142755), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000629	SCV003844908	pathogenic	Phenylketonuria	2023-02-03	criteria provided, single submitter	clinical testing	Variant summary: PAH c.818C>T (p.Ser273Phe) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal doamin (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251344 control chromosomes (gnomAD). c.818C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example: Melle_1991, Rozen_1994, Zschocke_1995, Tyfield_1997, Greeves_2000, Ho_2013). These data indicate that the variant is very likely to be associated with disease. Two submitters including ClinGen PAH Variant Curation Expert Panel have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000000629	SCV000020779	pathogenic	Phenylketonuria	1991-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089111	SCV000119718	not provided	not provided		no assertion provided	not provided