NM_000277.3(PAH):c.165T>G (p.Phe55Leu) AND Phenylketonuria

Germline classification:: Pathogenic/Likely pathogenic (10 submissions)
Last evaluated:: Mar 30, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000150092.42

Allele description [Variation Report for NM_000277.3(PAH):c.165T>G (p.Phe55Leu)]

NM_000277.3(PAH):c.165T>G (p.Phe55Leu)

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.165T>G (p.Phe55Leu)

HGVS:

NC_000012.12:g.102912794A>C
NG_008690.2:g.50617T>G
NM_000277.3:c.165T>GMANE SELECT
NM_001354304.2:c.165T>G
NP_000268.1:p.Phe55Leu
NP_000268.1:p.Phe55Leu
NP_001341233.1:p.Phe55Leu
NC_000012.11:g.103306572A>C
NM_000277.1:c.165T>G
P00439:p.Phe55Leu

Protein change:

F55L

Links:

UniProtKB: P00439#VAR_000879; dbSNP: rs199475598

NCBI 1000 Genomes Browser:

rs199475598

Molecular consequence:

NM_000277.3:c.165T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.165T>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
SCV000611224	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 19, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000827978	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 9298832, 9521426, 10598814, 12501224, 18299955, 23932990, 18538294, 28492532
SCV000914560	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Oct 31, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 23430918, 9298832, 9521426, 11678552, 23932990, 12655553, 18538294, 18299955 Citation Link,
SCV001194100	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 (10) [See all records that cite these PMIDs] 30367646, 27121329, 26655635, 9298832, 18538294, 18299955, 11678552, 23932990, 23430918, 9521426 Citation Link,
SCV001459228	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001810549	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jul 22, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002016482	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 6, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002572851	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004201328	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 30, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004848752	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 26, 2022)	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	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

Citations

PubMed

Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation.

Mallolas J, Vilaseca MA, Campistol J, Lambruschini N, Cambra FJ, Estivill X, Milà M.

Hum Genet. 1999 Nov;105(5):468-73.

PubMed [citation]

PMID:: 10598814

Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria.

Muntau AC, Röschinger W, Habich M, Demmelmair H, Hoffmann B, Sommerhoff CP, Roscher AA.

N Engl J Med. 2002 Dec 26;347(26):2122-32.

PubMed [citation]

PMID:: 12501224

See all PubMed Citations (15)

Details of each submission

From Fulgent Genetics, Fulgent Genetics, SCV000611224.2

#	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 Invitae, SCV000827978.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 55 of the PAH protein (p.Phe55Leu). This variant is present in population databases (rs199475598, gnomAD 0.09%). This missense change has been observed in individual(s) with hyperphenylalaninemia or phenylketonuria (PMID: 9298832, 9521426, 10598814, 12501224, 18299955, 23932990). ClinVar contains an entry for this variant (Variation ID: 92734). 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: 18538294). 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 Illumina Laboratory Services, Illumina, SCV000914560.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

The PAH c.165T>G (p.Phe55Leu) missense variant has been reported in over nine studies and is found in at least twelve probands in a compound heterozygous state (Zekanowski et al. 1997; Bosco et al. 1998; Guldberg et al. 1998; Zekanowski et al. 2001; Muntau et al. 2002; Aulehla-Scholz et al. 2003; Bercovoch et al. 2008; Sarkissan et al. 2010; Zhu et al. 2013). The p.Phe55Leu variant was absent from 320 controls and is reported at a frequency of 0.00093 in the Latino population of the Genome Aggregation Database. Functional studies by Gertsing et al. (2008) demonstrated that the Phe55 residue is part of the hydrophobic core of the regulatory domain of the protein. The variant showed only a moderate reduction in enzyme activity compared to wild type and was shown to induce misfolding and facilitate unfolding but did not affect the conformational stability of the catalytic domain. Based on the evidence, the p.Phe55Leu 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 Myriad Genetics, Inc., SCV001194100.2

#	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.165T>G(F55L) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 30367646, 27121329, 26655635, 9298832, 18538294, 18299955, 11678552, 23932990, 23430918 and 9521426. Classification of NM_000277.1(PAH):c.165T>G(F55L) 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 Natera, Inc., SCV001459228.1

#	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, SCV001810549.1

#	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 Revvity Omics, Revvity, SCV002016482.3

#	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 3billion, SCV002572851.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000092734). A different missense change at the same codon (p.Phe55Ser) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000120266). Therefore, this variant is classified as 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 Baylor Genetics, SCV004201328.2

#	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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848752.1

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

Description

The c.165T>G (p.Phe55Leu) variant in PAH has been reported in at least 27 individuals with phenylalanine hydroxylase deficiency/phenylketonuria (PKU)/hyperphenylalaninemia (HPA) (Zhu 2013 PMID: 23932990, Zekanowski PMID: 9298832,Vela-Amieva 2021 PMID: 34828281, Ozturk 2022 PMID: 35405047, Ferreira 2021 PMID: 33465300, Bosco 1998 PMID: 9521426, Bercovich 2008 PMID: 1829995, Aldamiz-Echevarria 2016 PMID: 27121329), and at least 12 of these individuals were compound heterozygous for a second pathogenic PAH variant. It has been identified in 0.002% of AMR chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID: 92734). Computational prediction tools suggest that this variant may impact the protein, though this information is not predictive enough to to determine pathogenecity. In vitro functional studies support an impact of p.Arg155His on protein function (Gersting S, et al. 2008 PMID: 18538294). This variant occurs in exon 2 of PAH where numerous pathogenic variants in PAH have been identified, including at the same residue (p.Phe55Ser). In summary, c.165T>G (p.Phe55Leu) meets criteria to be classified as pathogenic for autosomal recessive PKU. ACMG/AMP Criteria applied: PM3_VeryStrong, PM5_Strong, PM2_Supporting, PP3, PS3_Supporting.

#	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 29, 2024

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