ClinVar Miner

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

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Total submissions: 16
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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).
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).
Institute of Human Genetics, University of Leipzig Medical Center RCV000000620 SCV001440177 pathogenic Phenylketonuria 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous.
Ambry Genetics RCV001265833 SCV001444005 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
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
Natera, Inc. RCV000000620 SCV001453099 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing

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