NM_000277.3(PAH):c.117C>G (p.Phe39Leu) AND Phenylketonuria

Germline classification:: Pathogenic (13 submissions)
Last evaluated:: Mar 27, 2020
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:: RCV000000636.102

Allele description [Variation Report for NM_000277.3(PAH):c.117C>G (p.Phe39Leu)]

NM_000277.3(PAH):c.117C>G (p.Phe39Leu)

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.117C>G (p.Phe39Leu)

Other names:

p.F39L:TTC>TTG

HGVS:

NC_000012.12:g.102912842G>C
NG_008690.2:g.50569C>G
NM_000277.3:c.117C>GMANE SELECT
NM_001354304.2:c.117C>G
NP_000268.1:p.Phe39Leu
NP_000268.1:p.Phe39Leu
NP_001341233.1:p.Phe39Leu
NC_000012.11:g.103306620G>C
NM_000277.1:c.117C>G
NM_000277.3(PAH):c.117C>GMANE SELECT
P00439:p.Phe39Leu
c.117C>G (p.Phe39Leu)

Protein change:

F39L; PHE39LEU

Links:

UniProtKB: P00439#VAR_000870; OMIM: 612349.0031; dbSNP: rs62642926

NCBI 1000 Genomes Browser:

rs62642926

Molecular consequence:

NM_000277.3:c.117C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.117C>G - 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
SCV000020786	OMIM	no assertion criteria provided	Pathogenic (Jul 1, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000375571	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Apr 27, 2017)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11461190, 23764561, 8592329, 8406445, 2063869, 15557004, 12173030, 17935162, 9399896, 8533759 Citation Link,
SCV000629175	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 2063869, 8592329, 8659548, 12655544, 12655553, 1146119, 15557004, 17935162, 21953985, 25563416, 28492532
SCV000696429	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 16, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23430918, 24368688 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV001163354	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 27, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001194131	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 20, 2019)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 8592329, 21953985, 10429004, 24368688, 26666653, 12173030 Citation Link,
SCV001251475	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 (7) [See all records that cite these PMIDs] 20301677, 8592329, 8533759, 8659548, 12655553, 1555700, 25741868
SCV001459230	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001762340	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Mar 27, 2020)	germline	curation	Citation Link,
SCV002016488	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 10, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002761795	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002794910	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 2, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005200805	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 20, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
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

Citations

PubMed

Homomeric and heteromeric interactions between wild-type and mutant phenylalanine hydroxylase subunits: evaluation of two-hybrid approaches for functional analysis of mutations causing hyperphenylalaninemia.

Waters PJ, Scriver CR, Parniak MA.

Mol Genet Metab. 2001 Jul;73(3):230-8.

PubMed [citation]

PMID:: 11461190

Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness.

Polak E, Ficek A, Radvanszky J, Soltysova A, Urge O, Cmelova E, Kantarska D, Kadasi L.

Gene. 2013 Sep 10;526(2):347-55. doi: 10.1016/j.gene.2013.05.057. Epub 2013 Jun 10.

PubMed [citation]

PMID:: 23764561

See all PubMed Citations (24)

Details of each submission

From OMIM, SCV000020786.65

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

Description

See Forrest et al. (1991).

#	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 Illumina Laboratory Services, Illumina, SCV000375571.3

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

Description

The PAH c.117C>G (p.Phe39Leu) missense variant is well-described in the literature and has been identified individuals with varying phenotypes, ranging from classic phenylketonuria (PKU) to untreated hyperphenylalaninemia with normal intelligence (Forrest et al. 1991; Tyfield et al. 1995; Kayaalp 1997). Across a selection of the available literature the p.Phe39Leu variant has been reported in a compound heterozygous state in at least seven patients and in at least 101 of 1738 patient alleles where zygosity was not specified (Forrest et al. 1991; Guldberg et al. 1993; Tyfield et al. 1995; Zschocke et al. 1995; O'Donnell et al. 2002; Erlandsen et al. 2004; ZurflÃ¼h et al 2008; Polak et al. 2013). The p.Phe39Leu variant is more common in Scottish and Northern Irish PKU populations, with a frequency of approximately 6% and 9.5% respectively (Tyfield et al., 1995; Zschocke et al., 1995). In vitro functional analysis by Waters et al. (1999 and 2000) revealed that the variant is associated with increased protein aggregation and accelerated proteolytic degradation compared to wild type, as well as partial conversion of normal oligomeric protein forms to higher molecular weight aggregates. The p.Phe39Leu variant was absent from at least 236 controls and is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant is generally described as a BH4-responsive variant (Erlandsen et al. 2004; ZurflÃ¼h et al. 2008; Heintz et al. 2012). Based on the collective evidence, the p.Phe39Leu variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000629175.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 39 of the PAH protein (p.Phe39Leu). This variant is present in population databases (rs62642926, gnomAD 0.02%). This missense change has been observed in individual(s) with phenylketonuria, mild phenylketonuria and hyperphenylalaninemia (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). It is commonly reported in individuals of Scotland and Northern Ireland ancestry (PMID: 2063869, 8592329, 8659548, 12655544, 12655553, 17935162). ClinVar contains an entry for this variant (Variation ID: 605). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 1146119, 15557004, 17935162, 21953985, 25563416). 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, SCV000696429.1

#	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.117C>G (p.Phe39Leu) variant located in the ACT domain (via InterPro) involves the alteration of a conserved nucleotide, which 3/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/121396 (1/11037), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications have cited the variant in homozygous and compound heterozygous affected individuals. Publications have indicated that the variant causes a mild-moderate phenotype. 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 Baylor Genetics, SCV001163354.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001194131.2

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

Description

NM_000277.1(PAH):c.117C>G(F39L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 8592329, 21953985, 10429004, 24368688, 26666653, and 12173030. Classification of NM_000277.1(PAH):c.117C>G(F39L) 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, SCV001251475.1

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

Description

The PAH c.117C>G (p.F39L) missense variant has been reported in individuals with affected with phenylketonuria (PKU), mild PKU and hyperphenylalaninemia (PMID: 8592329; 8533759; 8659548; 12655553; 15557004).

#	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		1	not provided	not provided	not provided

From Natera, Inc., SCV001459230.1

#	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 ClinGen PAH Variant Curation Expert Panel, SCV001762340.1

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

Description

The c.117C>G (p.Phe39Leu) variant in PAH has been reported in multiple individuals with PKU. (PMID: 23430918, 8659548, 8406445, 2063869). This variant has an extremely low allele frequency in ExAC, gnomAD, 1000 Genomes, ESP (MAF=0.00016). This variant was detected with multiple pathogenic variants: T81P, V177L (PMID: 8659548), F55fsdelT (2 patients, PMID: 15557004), p.I65T, p.R408W (4 patients), p.R252W, p.E280K, c.1066-11G>A, c.1315+1G>A (PMID: 23430918). There is cosegregation with disease in affected siblings in 2 families PMID: 2063869, 8592329). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2, PP4, PP1.

#	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 Revvity Omics, Revvity, SCV002016488.3

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761795.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002794910.1

#	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 Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV005200805.1

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

Description

PM3_very-strong, PM2, PP4, PP1

#	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

Last Updated: Nov 3, 2024

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