ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.896T>G (p.Phe299Cys)
Germline
Classification
Help
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.
(16)
Help
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.
Pathogenic
16
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.896T>G (p.Phe299Cys)
Variation ID: 613 Accession: VCV000000613.109
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102851703 (GRCh38) [ NCBI UCSC ] 12: 103245481 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Nov 24, 2024 Jul 8, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.896T>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Phe299Cys missense NM_001354304.2:c.896T>G NP_001341233.1:p.Phe299Cys missense NC_000012.12:g.102851703A>C NC_000012.11:g.103245481A>C NG_008690.2:g.111708T>G P00439:p.Phe299Cys - Protein change
- F299C
- Other names
-
p.F299C:TTT>TGT
- Canonical SPDI
- NC_000012.12:102851702:A:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00007
Trans-Omics for Precision Medicine (TOPMed) 0.00008
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00012
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| LOC126861615 | - | - | - | GRCh38 | - | 84 |
| PAH | - | - |
GRCh38 GRCh37 |
1508 | 1631 | |
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. |
|---|---|---|---|---|
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 27, 2024 | RCV000000644.100 | |
| Pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jul 8, 2024 | RCV000089148.29 | |
|
PAH-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Mar 23, 2024 | RCV004739275.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 08, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000232506.5
First in ClinVar: Jun 28, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 16
Sex: mixed
|
|
|
Pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893939.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(May 16, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362285.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PAH c.896T>G (p.Phe299Cys) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain of the encoded protein sequence. Five … (more)
Variant summary: PAH c.896T>G (p.Phe299Cys) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251056 control chromosomes. c.896T>G has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. The variant is reported to have 0% in vitro enzyme activity (Eiken_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Feb 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV001134526.3
First in ClinVar: Jan 05, 2020 Last updated: Jan 01, 2022 |
Comment:
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in … (more)
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
|
|
|
Pathogenic
(Aug 14, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000915569.1
First in ClinVar: May 24, 2019 Last updated: May 24, 2019 |
Comment:
The PAH c.896T>G (p.Phe299Cys) missense variant has been reported in at least six studies and identified in 12 individuals with phenylketonuria (PKU) or hyperphenylalaninemia (HPA) … (more)
The PAH c.896T>G (p.Phe299Cys) missense variant has been reported in at least six studies and identified in 12 individuals with phenylketonuria (PKU) or hyperphenylalaninemia (HPA) including in one individual with the variant in a homozygous state and 11 individuals in a compound heterozygous state (Eiken et al. 1992; Waters et al. 1998; Aulehla-Scholz and Heilbronner 2003). The variant was also identified in ten alleles where zygosity was not specified in individuals with classical PKU or HPA (Zschoke et al. 1995; Kozák et al. 1997). Control data are unavailable for the p.Phe299Cys variant which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Carter et al. (1998) also report the variant at an average frequency of 6.4% in newborns with PKU or non-PKU HPA identified through newborn screening in Quebec. Based on the evidence, the p.Phe299Cys 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)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Phenylketonuria
Affected status: yes
Allele origin:
germline
|
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251470.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The PAH c.896T>G (p.F299C) missense variant has been reported in the homozygous or compound heterozygous state in multiple individuals with phenylketonuria (PMID: 8659548; 12655553; 1312992).
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Feb 14, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000239077.10
First in ClinVar: Jul 18, 2015 Last updated: Apr 17, 2019 |
Comment:
Published functional studies demonstrate a damaging effect, specifically that F299C mutant protein is associated with significantly reduced enzyme activity (Knappskog et al., 1993; Waters et … (more)
Published functional studies demonstrate a damaging effect, specifically that F299C mutant protein is associated with significantly reduced enzyme activity (Knappskog et al., 1993; Waters et al., 1998); Individuals with classic PKU who harbored F299C and a second variant in PAH were described as non-responsive to tetrahydrobiopterin (BH4) therapy (Jeannesson-Thivisol et al., 2015); This variant is associated with the following publications: (PMID: 11368310, 9399896, 9781015, 8889590, 9642259, 15597538, 24517888, 24368688, 12655547, 8831077, 1971147, 8533759, 7913581, 12655553, 8304187, 17924342, 25087612, 10980574, 19244369, 9391881, 26666653, 9450897, 1312992, 32668217, 32853555) (less)
|
|
|
Pathogenic
(Jan 14, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000754080.8
First in ClinVar: May 03, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 299 of the PAH protein … (more)
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 299 of the PAH protein (p.Phe299Cys). This variant is present in population databases (rs62642933, gnomAD 0.02%). This variant has been reported as homozygous or in combination with other pathogenic PAH variants in several individuals affected with hyperphenylalaninemia and phenylketonuria. This variant has been described as a common cause of the disease in Norway and the British Islands, although it has also been observed in other populations (PMID: 7726156, 8831077, 9012412, 9781015, 12173030, 1312992, 26666653). ClinVar contains an entry for this variant (Variation ID: 613). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 8304187). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Mar 27, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201360.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Apr 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010187.12
First in ClinVar: Jul 16, 2023 Last updated: Oct 20, 2024 |
Comment:
PAH: PM3:Very Strong, PM2, PP4:Moderate, PP3, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Jul 08, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005414108.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
PP3, PP4, PM2_moderate, PM3_very_strong
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463135.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
Pathogenic
(Mar 23, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PAH-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005360671.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The PAH c.896T>G variant is predicted to result in the amino acid substitution p.Phe299Cys. This variant has been recurrently reported in the homozygous state or … (more)
The PAH c.896T>G variant is predicted to result in the amino acid substitution p.Phe299Cys. This variant has been recurrently reported in the homozygous state or in the heterozygous state with a second PAH variant in individuals with phenylalanine hydroxylase deficiency (e.g., Eiken et al. 1996. PubMed ID: 8875186; Carter et al. 1998. PubMed ID: 9781015; Hillert et al. 2020. PubMed ID: 32668217). It has been reported to reduce enzyme activity to <3% in an in vitro study, and is considered to be a classic phenylketonuria (PKU) variant (Knappskog et al. 1993. PubMed ID: 8304187; http://www.biopku.org/pah/result-details-pah.asp?ID=341#). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(Mar 01, 1992)
|
no assertion criteria provided
Method: literature only
|
PHENYLKETONURIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020794.67
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
The mutant haplotype 8 occurs relatively frequently in Norwegian phenylketonuria (PKU; 261600) patients (comprising 6% of mutant genes), whereas it is rare among other European … (more)
The mutant haplotype 8 occurs relatively frequently in Norwegian phenylketonuria (PKU; 261600) patients (comprising 6% of mutant genes), whereas it is rare among other European PKU patients. Normal haplotype 8 genes have not been observed in any European population. Eiken et al. (1992) found that all mutant haplotype 8 chromosomes carried the phe299-to-cys (F299C) mutation described briefly by Okano et al. (1989). A patient homozygous for the F299C mutation manifested severe PKU. (less)
|
|
|
Pathogenic
(Jul 18, 2016)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000220607.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 23, 2019 |
|
|
|
not provided
(-)
|
no classification provided
Method: not provided
|
not provided
Affected status: not provided
Allele origin:
not provided
|
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119760.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
| click to load more click to collapse | |||||
Citation text
Okano, Y., Wang, T., Eisensmith, R. C., Woo, S. L. C. PKU mutations among Caucasians. (Abstract) Am. J. Hum. Genet. 45: A211-only, 1989.
Comment:
Variant summary: PAH c.896T>G (p.Phe299Cys) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251056 control chromosomes. c.896T>G has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. The variant is reported to have 0% in vitro enzyme activity (Eiken_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Comment:
The PAH c.896T>G (p.Phe299Cys) missense variant has been reported in at least six studies and identified in 12 individuals with phenylketonuria (PKU) or hyperphenylalaninemia (HPA) including in one individual with the variant in a homozygous state and 11 individuals in a compound heterozygous state (Eiken et al. 1992; Waters et al. 1998; Aulehla-Scholz and Heilbronner 2003). The variant was also identified in ten alleles where zygosity was not specified in individuals with classical PKU or HPA (Zschoke et al. 1995; Kozák et al. 1997). Control data are unavailable for the p.Phe299Cys variant which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Carter et al. (1998) also report the variant at an average frequency of 6.4% in newborns with PKU or non-PKU HPA identified through newborn screening in Quebec. Based on the evidence, the p.Phe299Cys 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.
Comment:
The PAH c.896T>G (p.F299C) missense variant has been reported in the homozygous or compound heterozygous state in multiple individuals with phenylketonuria (PMID: 8659548; 12655553; 1312992).
Comment:
Published functional studies demonstrate a damaging effect, specifically that F299C mutant protein is associated with significantly reduced enzyme activity (Knappskog et al., 1993; Waters et al., 1998); Individuals with classic PKU who harbored F299C and a second variant in PAH were described as non-responsive to tetrahydrobiopterin (BH4) therapy (Jeannesson-Thivisol et al., 2015); This variant is associated with the following publications: (PMID: 11368310, 9399896, 9781015, 8889590, 9642259, 15597538, 24517888, 24368688, 12655547, 8831077, 1971147, 8533759, 7913581, 12655553, 8304187, 17924342, 25087612, 10980574, 19244369, 9391881, 26666653, 9450897, 1312992, 32668217, 32853555)
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 299 of the PAH protein (p.Phe299Cys). This variant is present in population databases (rs62642933, gnomAD 0.02%). This variant has been reported as homozygous or in combination with other pathogenic PAH variants in several individuals affected with hyperphenylalaninemia and phenylketonuria. This variant has been described as a common cause of the disease in Norway and the British Islands, although it has also been observed in other populations (PMID: 7726156, 8831077, 9012412, 9781015, 12173030, 1312992, 26666653). ClinVar contains an entry for this variant (Variation ID: 613). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 8304187). For these reasons, this variant has been classified as Pathogenic.
Comment:
PAH: PM3:Very Strong, PM2, PP4:Moderate, PP3, PS3:Supporting
Comment:
PP3, PP4, PM2_moderate, PM3_very_strong
Comment:
The PAH c.896T>G variant is predicted to result in the amino acid substitution p.Phe299Cys. This variant has been recurrently reported in the homozygous state or in the heterozygous state with a second PAH variant in individuals with phenylalanine hydroxylase deficiency (e.g., Eiken et al. 1996. PubMed ID: 8875186; Carter et al. 1998. PubMed ID: 9781015; Hillert et al. 2020. PubMed ID: 32668217). It has been reported to reduce enzyme activity to <3% in an in vitro study, and is considered to be a classic phenylketonuria (PKU) variant (Knappskog et al. 1993. PubMed ID: 8304187; http://www.biopku.org/pah/result-details-pah.asp?ID=341#). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.
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. |
Comment:
Variant summary: PAH c.896T>G (p.Phe299Cys) results in a non-conservative amino acid change located in the Eukaryotic phenylalanine-4-hydroxylase, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251056 control chromosomes. c.896T>G has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. The variant is reported to have 0% in vitro enzyme activity (Eiken_1996). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Occurs in multiple cases with a recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Comment:
The PAH c.896T>G (p.Phe299Cys) missense variant has been reported in at least six studies and identified in 12 individuals with phenylketonuria (PKU) or hyperphenylalaninemia (HPA) including in one individual with the variant in a homozygous state and 11 individuals in a compound heterozygous state (Eiken et al. 1992; Waters et al. 1998; Aulehla-Scholz and Heilbronner 2003). The variant was also identified in ten alleles where zygosity was not specified in individuals with classical PKU or HPA (Zschoke et al. 1995; Kozák et al. 1997). Control data are unavailable for the p.Phe299Cys variant which is reported at a frequency of 0.000349 in the European American population of the Exome Sequencing Project. Carter et al. (1998) also report the variant at an average frequency of 6.4% in newborns with PKU or non-PKU HPA identified through newborn screening in Quebec. Based on the evidence, the p.Phe299Cys 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.
Comment:
The PAH c.896T>G (p.F299C) missense variant has been reported in the homozygous or compound heterozygous state in multiple individuals with phenylketonuria (PMID: 8659548; 12655553; 1312992).
Comment:
Published functional studies demonstrate a damaging effect, specifically that F299C mutant protein is associated with significantly reduced enzyme activity (Knappskog et al., 1993; Waters et al., 1998); Individuals with classic PKU who harbored F299C and a second variant in PAH were described as non-responsive to tetrahydrobiopterin (BH4) therapy (Jeannesson-Thivisol et al., 2015); This variant is associated with the following publications: (PMID: 11368310, 9399896, 9781015, 8889590, 9642259, 15597538, 24517888, 24368688, 12655547, 8831077, 1971147, 8533759, 7913581, 12655553, 8304187, 17924342, 25087612, 10980574, 19244369, 9391881, 26666653, 9450897, 1312992, 32668217, 32853555)
Comment:
This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 299 of the PAH protein (p.Phe299Cys). This variant is present in population databases (rs62642933, gnomAD 0.02%). This variant has been reported as homozygous or in combination with other pathogenic PAH variants in several individuals affected with hyperphenylalaninemia and phenylketonuria. This variant has been described as a common cause of the disease in Norway and the British Islands, although it has also been observed in other populations (PMID: 7726156, 8831077, 9012412, 9781015, 12173030, 1312992, 26666653). ClinVar contains an entry for this variant (Variation ID: 613). 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 expected to disrupt PAH protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 8304187). For these reasons, this variant has been classified as Pathogenic.
Comment:
PAH: PM3:Very Strong, PM2, PP4:Moderate, PP3, PS3:Supporting
Comment:
PP3, PP4, PM2_moderate, PM3_very_strong
Comment:
The PAH c.896T>G variant is predicted to result in the amino acid substitution p.Phe299Cys. This variant has been recurrently reported in the homozygous state or in the heterozygous state with a second PAH variant in individuals with phenylalanine hydroxylase deficiency (e.g., Eiken et al. 1996. PubMed ID: 8875186; Carter et al. 1998. PubMed ID: 9781015; Hillert et al. 2020. PubMed ID: 32668217). It has been reported to reduce enzyme activity to <3% in an in vitro study, and is considered to be a classic phenylketonuria (PKU) variant (Knappskog et al. 1993. PubMed ID: 8304187; http://www.biopku.org/pah/result-details-pah.asp?ID=341#). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Generation of fibroblast-derived induced pluripotent stem cell (iPSC) lines from two paediatric patients with phenylketonuria. | Veleva D | Stem cell research | 2024 | PMID: 38555716 |
| Natural Protein Intake in Children with Phenylketonuria: Prescription vs. Actual Intakes. | Pinto A | Nutrients | 2023 | PMID: 38068761 |
| Preliminary Data on Free Use of Fruits and Vegetables Containing Phenylalanine 76-100 mg/100 g of Food in 16 Children with Phenylketonuria: 6 Months Follow-Up. | Pinto A | Nutrients | 2023 | PMID: 37447372 |
| Identification of incompletely penetrant variants and interallelic interactions in autosomal recessive disorders by a population-genetic approach. | Mikó Á | Human mutation | 2021 | PMID: 34405919 |
| Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. | Roman TS | American journal of human genetics | 2020 | PMID: 32853555 |
| The role of exome sequencing in newborn screening for inborn errors of metabolism. | Adhikari AN | Nature medicine | 2020 | PMID: 32778825 |
| The Genetic Landscape and Epidemiology of Phenylketonuria. | Hillert A | American journal of human genetics | 2020 | PMID: 32668217 |
| Phenylalanine Hydroxylase Deficiency. | Adam MP | - | 2017 | PMID: 20301677 |
| Genotype-phenotype associations in French patients with phenylketonuria and importance of genotype for full assessment of tetrahydrobiopterin responsiveness. | Jeannesson-Thivisol E | Orphanet journal of rare diseases | 2015 | PMID: 26666653 |
| Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response? | Sarkissian CN | JIMD reports | 2012 | PMID: 23430918 |
| Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases. | Pey AL | American journal of human genetics | 2007 | PMID: 17924342 |
| Inter-individual variation in brain phenylalanine concentration in patients with PKU is not caused by genetic variation in the 4F2hc/LAT1 complex. | Møller LB | Molecular genetics and metabolism | 2005 | PMID: 16176881 |
| Mutational spectrum in German patients with phenylalanine hydroxylase deficiency. | Aulehla-Scholz C | Human mutation | 2003 | PMID: 12655553 |
| DHPLC mutation analysis of phenylketonuria. | Bräutigam S | Molecular genetics and metabolism | 2003 | PMID: 12649065 |
| The mutation spectrum of hyperphenylalaninaemia in the Republic of Ireland: the population history of the Irish revisited. | O'Donnell KA | European journal of human genetics : EJHG | 2002 | PMID: 12173030 |
| Molecular analysis of phenylketonuria (PKU) in newborns from Texas. | Yang Y | Human mutation | 2001 | PMID: 11385716 |
| Structural interpretation of mutations in phenylalanine hydroxylase protein aids in identifying genotype-phenotype correlations in phenylketonuria. | Jennings IG | European journal of human genetics : EJHG | 2000 | PMID: 10980574 |
| Alterations in protein aggregation and degradation due to mild and severe missense mutations (A104D, R157N) in the human phenylalanine hydroxylase gene (PAH). | Waters PJ | Human mutation | 1998 | PMID: 9792411 |
| Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience. | Carter KC | European journal of human genetics : EJHG | 1998 | PMID: 9781015 |
| Structure of tetrameric human phenylalanine hydroxylase and its implications for phenylketonuria. | Fusetti F | The Journal of biological chemistry | 1998 | PMID: 9642259 |
| A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. | Guldberg P | American journal of human genetics | 1998 | PMID: 9634518 |
| Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. | Kayaalp E | American journal of human genetics | 1997 | PMID: 9399896 |
| Mutation and haplotype analysis of phenylalanine hydroxylase alleles in classical PKU patients from the Czech Republic: identification of four novel mutations. | Kozák L | Journal of medical genetics | 1997 | PMID: 9391881 |
| Sequence variation at the phenylalanine hydroxylase gene in the British Isles. | Tyfield LA | American journal of human genetics | 1997 | PMID: 9012412 |
| Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations. | Guldberg P | Human mutation | 1996 | PMID: 8889590 |
| Phenylketonuria genotypes correlated to metabolic phenotype groups in Norway. | Eiken HG | European journal of pediatrics | 1996 | PMID: 8831077 |
| Phenylalanine hydroxylase gene mutations in the United States: report from the Maternal PKU Collaborative Study. | Guldberg P | American journal of human genetics | 1996 | PMID: 8659548 |
| Molecular basis of phenylketonuria and a correlation between genotype and phenotype in a heterogeneous southeastern US population. | Eisensmith RC | Pediatrics | 1996 | PMID: 8632937 |
| Phenylketonuria mutation analysis in Northern Ireland: a rapid stepwise approach. | Zschocke J | American journal of human genetics | 1995 | PMID: 8533759 |
| Characterization of phenylalanine hydroxylase alleles in untreated phenylketonuria patients from Victoria, Australia: origin of alleles and haplotypes. | Ramus SJ | American journal of human genetics | 1995 | PMID: 7726156 |
| Mutation profiles of phenylketonuria in Quebec populations: evidence of stratification and novel mutations. | Rozen R | American journal of human genetics | 1994 | PMID: 7913581 |
| Expression of wild type and mutant forms of human phenylalanine hydroxylase in E. coli. | Knappskog M | Advances in experimental medicine and biology | 1993 | PMID: 8304187 |
| PKU mutations R408Q and F299C in Norway: haplotype associations, geographic distributions and phenotype characteristics. | Eiken HG | Human genetics | 1992 | PMID: 1312992 |
| Molecular basis of phenylketonuria and related hyperphenylalaninemias: mutations and polymorphisms in the human phenylalanine hydroxylase gene. | Eisensmith RC | Human mutation | 1992 | PMID: 1301187 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
| Okano, Y., Wang, T., Eisensmith, R. C., Woo, S. L. C. PKU mutations among Caucasians. (Abstract) Am. J. Hum. Genet. 45: A211-only, 1989. | - | - | - | - |
| click to load more click to collapse | ||||
Text-mined citations for rs62642933 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Nov 25, 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.