ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.355C>T (p.Pro119Ser)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000277.3(PAH):c.355C>T (p.Pro119Ser)
Variation ID: 92741 Accession: VCV000092741.27
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102877548 (GRCh38) [ NCBI UCSC ] 12: 103271326 (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 Jun 28, 2015 Jun 17, 2024 Jul 29, 2018 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.355C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Pro119Ser missense NM_001354304.2:c.355C>T NP_001341233.1:p.Pro119Ser missense NC_000012.12:g.102877548G>A NC_000012.11:g.103271326G>A NG_008690.2:g.85863C>T - Protein change
- P119S
- Other names
- NM_000277.2(PAH):c.355C>T
- Canonical SPDI
- NC_000012.12:102877547:G:A
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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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0.00020 (A)
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
The Genome Aggregation Database (gnomAD), exomes 0.00029
Exome Aggregation Consortium (ExAC) 0.00035
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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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
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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 |
1504 | 1627 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Likely pathogenic (8) |
reviewed by expert panel
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Jul 29, 2018 | RCV000178066.32 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Feb 20, 2023 | RCV000790751.17 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 6, 2023 | RCV004019527.1 |
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. |
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Likely pathogenic
(Jul 29, 2018)
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reviewed by expert panel
Method: curation
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000852139.4 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID … (more)
PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM3_Strong, PP4_Moderate). (less)
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Uncertain significance
(Apr 25, 2018)
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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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Counsyl
Accession: SCV000800700.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
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Likely pathogenic
(May 24, 2017)
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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: SCV000230056.5
First in ClinVar: Jun 28, 2015 Last updated: Jul 31, 2019 |
Number of individuals with the variant: 3
Sex: mixed
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Likely pathogenic
(Apr 13, 2022)
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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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GeneDx
Accession: SCV002512912.2
First in ClinVar: May 21, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15171997, … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15171997, 12655554, 34426522, 30389586, 32778825, 29771303, 21147011, 31355225) (less)
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Pathogenic
(Feb 13, 2023)
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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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362288.2
First in ClinVar: Jun 22, 2020 Last updated: Mar 26, 2023 |
Comment:
Variant summary: PAH c.355C>T (p.Pro119Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR019774) of the encoded protein sequence. Five of … (more)
Variant summary: PAH c.355C>T (p.Pro119Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00029 in 251358 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.00029 vs 0.0079), allowing no conclusion about variant significance. c.355C>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) or Hyperphenylalaninemia (e.g. Lindner_2003, Dobrowolski_2011, Esfahani_2018, Kuznetcova_2019, Su_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic n=2, likely pathogenic n=5, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Jan 04, 2023)
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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: SCV002020217.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Dec 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV004998569.1
First in ClinVar: May 01, 2024 Last updated: May 01, 2024 |
Comment:
The c.355C>T (p.P119S) alteration is located in exon 4 (coding exon 4) of the PAH gene. This alteration results from a C to T substitution … (more)
The c.355C>T (p.P119S) alteration is located in exon 4 (coding exon 4) of the PAH gene. This alteration results from a C to T substitution at nucleotide position 355, causing the proline (P) at amino acid position 119 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.029% (72/251358) total alleles studied. The highest observed frequency was 0.229% (70/30616) of South Asian alleles. This alteration has been reported compound heterozygous with a second alteration in PAH in multiple patients with biochemically confirmed PKU or hyperphenylalaninemia (Lindner, 2003; Esfahani, 2019; Su, 2019). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
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Likely pathogenic
(Mar 19, 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: SCV001163726.2
First in ClinVar: Feb 28, 2020 Last updated: Jun 17, 2024 |
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Likely pathogenic
(Sep 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
inherited
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New York Genome Center
Study: CSER-NYCKidSeq
Accession: SCV002564213.1 First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
Clinical Features:
Intellectual disability (present) , Seizure (present) , Autism (present)
Secondary finding: no
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Pathogenic
(Jul 26, 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: SCV002804434.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Likely pathogenic
(Feb 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222243.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant is associated with phenylketonuria and hyperphenylalaninemia (PMIDs: 17924342 (2007), 21147011 (20111), and 35405047 (2022)). The variant has been reported as homozygous (PMID: 36537053 … (more)
This variant is associated with phenylketonuria and hyperphenylalaninemia (PMIDs: 17924342 (2007), 21147011 (20111), and 35405047 (2022)). The variant has been reported as homozygous (PMID: 36537053 (2022)) or compound heterozygous with other pathogenic PAH variants in multiple individuals with PAH-related conditions (PMIDs: 31355225 (2019), 30389586 (2019), and 32668217 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. (less)
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Pathogenic
(Jan 28, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000827282.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 119 of the PAH protein (p.Pro119Ser). … (more)
This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 119 of the PAH protein (p.Pro119Ser). This variant is present in population databases (rs398123292, gnomAD 0.2%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 12655554, 21147011, 30389586, 31355225). ClinVar contains an entry for this variant (Variation ID: 92741). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. (less)
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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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Hyperphenylalaninemias genotyping: Results of over 60 years of history in Lombardy, Italy. | Rovelli V | Endocrinology, diabetes & metabolism | 2023 | PMID: 36537053 |
An update of the mutation spectrum of phenylalanine hydroxylase (PAH) gene in the population of Turkey. | Ozturk FN | Journal of pediatric endocrinology & metabolism : JPEM | 2022 | PMID: 35405047 |
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 |
The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra. | Su Y | Annals of translational medicine | 2019 | PMID: 31355225 |
The study of the full spectrum of variants leading to hyperphenylalaninemia have revealed 10 new variants in the PAH gene. | Kuznetcova I | Metabolic brain disease | 2019 | PMID: 31332730 |
A comprehensive study of phenylalanine hydroxylase gene mutations in the Iranian phenylketonuria patients. | Esfahani MS | European journal of medical genetics | 2019 | PMID: 30389586 |
Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population. | Dobrowolski SF | Molecular genetics and metabolism | 2011 | PMID: 21147011 |
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 |
The metabolic and molecular bases of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Blau N | Molecular genetics and metabolism | 2004 | PMID: 15171997 |
Tetrahydrobiopterin sensitivity in German patients with mild phenylalanine hydroxylase deficiency. | Lindner M | Human mutation | 2003 | PMID: 12655554 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/38a183ee-7e53-4c24-a250-50958f390c78 | - | - | - | - |
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Text-mined citations for rs398123292 ...
HelpRecord last updated Oct 08, 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.