NM_000277.3(PAH):c.842C>T (p.Pro281Leu) AND Phenylketonuria

Germline classification:: Likely pathogenic (18 submissions)
Last evaluated:: Aug 27, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000000620.106

Allele description [Variation Report for NM_000277.3(PAH):c.842C>T (p.Pro281Leu)]

NM_000277.3(PAH):c.842C>T (p.Pro281Leu)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.842C>T (p.Pro281Leu)

Other names:

NM_000277.1(PAH):c.842C>T

HGVS:

NC_000012.12:g.102852815G>A
NG_008690.2:g.110596C>T
NM_000277.3:c.842C>TMANE SELECT
NM_001354304.2:c.842C>T
NP_000268.1:p.Pro281Leu
NP_000268.1:p.Pro281Leu
NP_001341233.1:p.Pro281Leu
NC_000012.11:g.103246593G>A
NM_000277.1:c.842C>T
P00439:p.Pro281Leu

Protein change:

P281L; PRO281LEU

Links:

UniProtKB: P00439#VAR_000981; OMIM: 612349.0012; dbSNP: rs5030851

NCBI 1000 Genomes Browser:

rs5030851

Molecular consequence:

NM_000277.3:c.842C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.842C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020770	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1994)	germline	literature only	PubMed (3) [See all records that cite these PMIDs] 2044609, 1769645, 7807961
SCV000324889	GeneReviews	no classification provided	not provided	germline	literature only
SCV000629222	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21871829, 25596310, 1672294, 17935162, 21953985, 28492532
SCV000696468	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 19, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23357515, 9399896 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000852092	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Likely pathogenic (Aug 27, 2018)	germline	curation	PubMed (4) [See all records that cite these PMIDs] 17935162, 15503242, 12655553, 25596310 Citation Link,
SCV000893941	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 31, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001163718	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193964	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 4, 2019)	unknown	clinical testing	PubMed (10) [See all records that cite these PMIDs] 22513348, 22526846, 19394257, 15503242, 20920871, 20187763, 22763404, 18299955, 17935162, 10471838 Citation Link,
SCV001251474	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	research	PubMed (6) [See all records that cite these PMIDs] 20301677, 1672290, 9634518, 10234516, 17935162, 25741868
SCV001440177	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2019)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001453099	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001810543	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002058848	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:12409276,
SCV002059760	Centogene AG - the Rare Disease Company	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003826584	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003842177	Payam Genetics Center, General Welfare Department of North Khorasan Province	no assertion criteria provided	Pathogenic (Mar 1, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29025426, 21915151, 21937252
SCV004244480	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004847976	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 29, 2015)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 1672294, 21953985, 10471838, 2014036, 17935162, 25596310, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	1	not provided	clinical testing, literature only, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Iranian	germline	no	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A prevalent missense mutation in Northern Europe associated with hyperphenylalaninaemia.

Okano Y, Eisensmith RC, Dasovich M, Wang T, Güttler F, Woo SL.

Eur J Pediatr. 1991 Mar;150(5):347-52.

PubMed [citation]

PMID:: 2044609

Aberrant splicing of phenylalanine hydroxylase mRNA: the major cause for phenylketonuria in parts of southern Europe.

Dworniczak B, Aulehla-Scholz C, Kalaydjieva L, Bartholomé K, Grudda K, Horst J.

Genomics. 1991 Oct;11(2):242-6.

PubMed [citation]

PMID:: 1769645

See all PubMed Citations (30)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From OMIM, SCV000020770.68

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (3)

Description

The pro281-to-leu (P281L) mutation in exon 7 was found on haplotype 1 in an Italian patient with phenylketonuria (PKU; 261600) (Okano et al., 1991). cDNA carrying the mutation was constructed and transfected into cultured mammalian cells. Expression analysis revealed negligible enzyme activity and undetectable levels of immunoreactive PAH protein. This mutation, like the arg252-to-trp mutation (R252W; 612349.0007), is in marked linkage disequilibrium with RFLP haplotype 1. The P281L mutation was found on 20% of haplotype 1 mutant chromosomes in the Italian population (Okano et al., 1991).

Dworniczak et al. (1991) found this mutation on 25% of all mutant haplotype 1 alleles in the German population. In addition, they identified this mutation on 1 mutant haplotype 4 allele. Expression analysis of the mutant allele in cultured mammalian cells demonstrated absence of immunoreactive PAH in cells transfected with this missense mutation, identical steady-state levels of mRNA in cells carrying both normal and mutant constructs, and absence of PAH activity in cells transfected with the mutant allele.

Baric et al. (1994) pointed to data indicating that the highest frequency of the P281L mutation is in Croatia where it was detected in 55% of haplotype 1 alleles, corresponding to 12% of all PKU alleles. They interpreted this finding as indicating that the mutation originated in southeastern Europe.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000324889.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000629222.9

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 281 of the PAH protein (p.Pro281Leu). This variant is present in population databases (rs5030851, gnomAD 0.02%). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 1672294, 21871829, 25596310; 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: 589). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PAH function (PMID: 1672294, 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696468.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV000852092.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (4)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000893941.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163718.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193964.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251474.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	research	PubMed (6)

Description

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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		2	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001440177.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This variant was identified as compound heterozygous.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001453099.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV001810543.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002058848.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000589, PMID:1672294, PS1_S). A different missense change at the same codon has been reported to be associated with PAH related disorder (ClinVar ID: VCV000092749, PMID:12409276,10598814,15171997, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.983, 3CNET: 0.998, PP3_P). A missense variant is a common mechanism associated with Classic phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000103, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Centogene AG - the Rare Disease Company, SCV002059760.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003826584.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Payam Genetics Center, General Welfare Department of North Khorasan Province, SCV003842177.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Iranian	2	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		2	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV004244480.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS3, PM3_Strong, PP3

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847976.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.Pro281Leu variant in PAH was first reported in patients with classic PKU by Okano et al., (Okano 1991, Okano 1991) and has been reported in numerous patients with PKU since then (Zurfluh 2008, Danecka 2015). In vitro functional studies provide evidence that the p.Pro281Leu variant impacts protein function (Okano 1991, Zurfluh 2008, Danecka 2015, Ellingsen 1999, Reblova 2015, Shi 2012). This variant has been identified in 0.018% (12/66740) of Euroepan chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs5030851). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant meets our criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 2, 2024

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