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

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Total submissions: 10

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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).
Counsyl	RCV000000620	SCV000677964	pathogenic	Phenylketonuria	2015-10-30	criteria provided, single submitter	clinical testing	The P281L mutation can be associated with any form of this disease.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078534	SCV000119744	not provided	not provided		no assertion provided	not provided
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000078534	SCV000110390	pathogenic	not provided	2017-01-26	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000000620	SCV000893941	pathogenic	Phenylketonuria	2018-10-31	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).
GeneReviews	RCV000000620	SCV000324889	pathogenic	Phenylketonuria	2016-10-20	no assertion criteria provided	literature only
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.
Invitae	RCV000000620	SCV000629222	pathogenic	Phenylketonuria	2018-08-27	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.
OMIM	RCV000000620	SCV000020770	pathogenic	Phenylketonuria	1994-01-01	no assertion criteria provided	literature only

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