ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.165T>G (p.Phe55Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000277.3(PAH):c.165T>G (p.Phe55Leu)
Variation ID: 92734 Accession: VCV000092734.36
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102912794 (GRCh38) [ NCBI UCSC ] 12: 103306572 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 19, 2014 Jun 17, 2024 Mar 30, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.165T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Phe55Leu missense NM_001354304.2:c.165T>G NP_001341233.1:p.Phe55Leu missense NC_000012.12:g.102912794A>C NC_000012.11:g.103306572A>C NG_008690.2:g.50617T>G P00439:p.Phe55Leu - Protein change
- F55L
- Other names
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- Canonical SPDI
- NC_000012.12:102912793:A:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00017
The Genome Aggregation Database (gnomAD) 0.00023
Trans-Omics for Precision Medicine (TOPMed) 0.00023
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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PAH | - | - |
GRCh38 GRCh37 |
1491 | 1610 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2023 | RCV000078512.23 | |
Pathogenic/Likely pathogenic (10) |
criteria provided, multiple submitters, no conflicts
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Mar 30, 2024 | RCV000150092.42 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 30, 2016 | RCV000588067.9 | |
See cases
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Pathogenic (1) |
criteria provided, single submitter
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Nov 13, 2020 | RCV002251964.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 30, 2016)
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criteria provided, single submitter
Method: clinical testing
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Hyperphenylalaninemia
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696440.1
First in ClinVar: Mar 20, 2018 Last updated: Mar 20, 2018 |
Comment:
Variant summary: The PAH c.165T>G (p.Phe55Leu) variant located in the ACT domain causes a missense change involving a conserved nucleotide, which 3/5 in silico tools … (more)
Variant summary: The PAH c.165T>G (p.Phe55Leu) variant located in the ACT domain causes a missense change involving 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 11/121376 (1/11037), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest has been reported in multiple affected individuals diagnosed with HPA as compound heterozygotes. In addition, multiple databases and clinical diagnostic laboratories have cited the variant with a classification of "pathogenic" or "likely pathogenic." Therefore, the variant of interest has been classified as "Pathogenic." (less)
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Likely pathogenic
(Nov 19, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611224.2
First in ClinVar: Jun 28, 2015 Last updated: Dec 31, 2022 |
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Pathogenic
(Mar 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002016482.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000827978.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
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). … (more)
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. (less)
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Pathogenic
(Aug 26, 2022)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848752.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Feb 01, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004131792.6
First in ClinVar: Nov 20, 2023 Last updated: Jun 17, 2024 |
Comment:
PAH: PM3:Very Strong, PM2, PS3:Supporting
Number of individuals with the variant: 1
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Pathogenic
(Mar 30, 2024)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004201328.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
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Pathogenic
(Aug 07, 2012)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110368.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000914560.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Dec 20, 2019)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV001194100.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
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, … (more)
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. (less)
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Likely pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810549.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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Pathogenic
(Nov 13, 2020)
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criteria provided, single submitter
Method: clinical testing
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See cases
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002523847.1
First in ClinVar: Jun 11, 2022 Last updated: Jun 11, 2022 |
Comment:
ACMG classification criteria: PS3, PS4, PM3, PP1, PP3, PP4
Clinical Features:
X-linked inheritance (present) , Autosomal recessive inheritance (present)
Geographic origin: Brazil
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572851.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
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 … (more)
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. (less)
Clinical Features:
Small for gestational age (present) , Severe short stature (present) , Growth delay (present) , Delayed skeletal maturation (present)
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001459228.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119438.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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White matter microstructural damage in early treated phenylketonuric patients. | González MJ | Orphanet journal of rare diseases | 2018 | PMID: 30367646 |
Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. | Aldámiz-Echevarría L | Journal of human genetics | 2016 | PMID: 27121329 |
Psychiatric disorders in adolescent and young adult patients with phenylketonuria. | Manti F | Molecular genetics and metabolism | 2016 | PMID: 26655635 |
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population. | Zhu T | Gene | 2013 | PMID: 23932990 |
Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? | Sarkissian CN | JIMD reports | 2012 | PMID: 23430918 |
Loss of function in phenylketonuria is caused by impaired molecular motions and conformational instability. | Gersting SW | American journal of human genetics | 2008 | PMID: 18538294 |
Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene. | Bercovich D | Journal of human genetics | 2008 | PMID: 18299955 |
Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. | Aulehla-Scholz C | Human mutation | 2003 | PMID: 12655553 |
Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. | Muntau AC | The New England journal of medicine | 2002 | PMID: 12501224 |
Should newborn mutation scanning for hyperphenylalaninaemia and galactosaemia be implemented? A Polish experience. | Zekanowski C | Journal of medical screening | 2001 | PMID: 11678552 |
Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation. | Mallolas J | Human genetics | 1999 | PMID: 10598814 |
Eight new mutations of the phenylalanine hydroxylase gene in Italian patients with hyperphenylalaninemia. | Bosco P | Human mutation | 1998 | PMID: 9521426 |
Mutations of the phenylalanine hydroxylase gene in mild hyperphenylalaninemia: a novel mutation in exon 3. | Zekanowski C | Human mutation | 1997 | PMID: 9298832 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
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Text-mined citations for rs199475598 ...
HelpRecord last updated Jun 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.