Submissions for variant NM_000277.3(PAH):c.842C>T (p.Pro281Leu) (rs5030851)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000620	SCV000852092	likely pathogenic	Phenylketonuria	2018-08-27	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PP3: ; PS3: 2% activity in bioPKU (PAH0309) (PMID:25596310; PMID:17935162); PP4_Moderate: 2 patients with moderate or classical PKU; patients with severe PKU. BH4 deficiency ruled out. (PMID:15503242; PMID:12655553); PM3: IVS4-1G>A (P/LP) (PMID:15503242). 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: (PP3, PS3, PP4_Moderate, PM3).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000078534	SCV000110390	pathogenic	not provided	2017-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000078534	SCV000329448	pathogenic	not provided	2018-05-18	criteria provided, single submitter	clinical testing	Expression studies found that the P281L variant is associated with very low PAH enzyme activity (0-1%) and is considered a severe PAH variant as patients homozygous for this variant have classic phenylketonuria (PKU) (Shi et al, 2012; Okano et al, 1991). The P281L variant is reported to not be responsive to BH4 therapy (Zurfluh et al., 2008).
Invitae	RCV000000620	SCV000629222	pathogenic	Phenylketonuria	2019-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 281 of the PAH protein (p.Pro281Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs5030851, ExAC 0.02%). This variant has been reported as homozygous or in combination with other pathogenic PAH variants in individuals affected with PAH-related diseases (PMID: 25596310, 1672294, 21871829). ClinVar contains an entry for this variant (Variation ID: 589). Experimental studies have shown that this missense change causes diminished PAH enzyme activity and protein expression, likely due to reduced protein stability (PMID: 21953985, 17935162, 1672294). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America	RCV000000620	SCV000696468	pathogenic	Phenylketonuria	2017-01-19	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.842C>T (p.Pro281Leu) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by at least one in vitro study showing the activity of PAH p.P281L was <1% of wild-type PAH activity (Kayaalp_1997). This variant was found in 12/121404 control chromosomes at a frequency of 0.0000988, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in numerous patients with classic PKU. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000000620	SCV000893941	pathogenic	Phenylketonuria	2018-10-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000620	SCV001163718	pathogenic	Phenylketonuria		criteria provided, single submitter	clinical testing
Myriad Women's Health, Inc.	RCV000000620	SCV001193964	pathogenic	Phenylketonuria	2019-12-04	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.842C>T(P281L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 22526846, 19394257, 15503242, 20920871, 20187763, 22763404, 18299955, 17935162 and 10471838. Classification of NM_000277.1(PAH):c.842C>T(P281L) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000078534	SCV001249178	pathogenic	not provided	2019-12-01	criteria provided, single submitter	clinical testing
UNC Molecular Genetics Laboratory,University of North Carolina at Chapel Hill	RCV000000620	SCV001251474	pathogenic	Phenylketonuria		criteria provided, single submitter	research	The PAH c.842C>T (p.P281L) variant is located at an intron/exon boundary, and this variant has been reported as pathogenic in individuals with phenylketonuria. This variant was also shown to abolish the function of the phenylalanine hydroxylase enzyme in vitro (PMID: 1672290; 9634518; 10234516; 17935162).
OMIM	RCV000000620	SCV000020770	pathogenic	Phenylketonuria	1994-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078534	SCV000119744	not provided	not provided		no assertion provided	not provided
GeneReviews	RCV000000620	SCV000324889	pathogenic	Phenylketonuria	2016-10-20	no assertion criteria provided	literature only