Across a selection of the available literature, the PAH c.1045T>C (p.Ser349Pro) missense variant has been identified in a total of 41 individuals with phenylalanine hydroxylase deficiency, including in a homozygous state in four patients, in a compound heterozygous state in 39 patients, and in a heterozygous state in one patient (Forrest et al. 1991; John et al. 1992; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996; Vela-Amieva et al. 2015; Aldámiz-EchevarrÃa et al. 2016). The variant was also identified in an additional eight alleles of unknown zygosity (Zurflüh et al. 2008; Couce et al. 2013). The p.Ser349Pro variant was absent from 152 control individuals but is reported at an allele frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Ser349Pro variant is associated with a severe phenotype and results in significantly reduced PAH activity levels of between 0% and 1.2%, and immunoreactivity levels of between 0% and 2.0% compared to wild type (Forrest et al. 1991; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996). Based on the collective evidence, the p.Ser349Pro 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.
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.1045T>C (p.Ser349Pro)
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.
(12)
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/Likely pathogenic
12
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.1045T>C (p.Ser349Pro)
Variation ID: 615 Accession: VCV000000615.98
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102844356 (GRCh38) [ NCBI UCSC ] 12: 103238134 (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 Jun 17, 2024 Mar 30, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.1045T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Ser349Pro missense NM_001354304.2:c.1045T>C NP_001341233.1:p.Ser349Pro missense NC_000012.12:g.102844356A>G NC_000012.11:g.103238134A>G NG_008690.2:g.119055T>C P00439:p.Ser349Pro - Protein change
- S349P
- Other names
-
p.S349P:TCA>CCA
S349R
- Canonical SPDI
- NC_000012.12:102844355:A:G
-
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.
-
0.00020 (G)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00007
The Genome Aggregation Database (gnomAD) 0.00008
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- Links
- Comment on variant
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. |
|||
| PAH | - | - |
GRCh38 GRCh37 |
1506 | 1629 | |
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/Likely pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
Mar 30, 2024 | RCV000000646.98 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jun 15, 2021 | RCV000078499.19 |
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 15, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000110355.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 14
Sex: mixed
|
|
|
Pathogenic
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000375564.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
Across a selection of the available literature, the PAH c.1045T>C (p.Ser349Pro) missense variant has been identified in a total of 41 individuals with phenylalanine hydroxylase … (more)
Across a selection of the available literature, the PAH c.1045T>C (p.Ser349Pro) missense variant has been identified in a total of 41 individuals with phenylalanine hydroxylase deficiency, including in a homozygous state in four patients, in a compound heterozygous state in 39 patients, and in a heterozygous state in one patient (Forrest et al. 1991; John et al. 1992; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996; Vela-Amieva et al. 2015; Aldámiz-EchevarrÃa et al. 2016). The variant was also identified in an additional eight alleles of unknown zygosity (Zurflüh et al. 2008; Couce et al. 2013). The p.Ser349Pro variant was absent from 152 control individuals but is reported at an allele frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Ser349Pro variant is associated with a severe phenotype and results in significantly reduced PAH activity levels of between 0% and 1.2%, and immunoreactivity levels of between 0% and 2.0% compared to wild type (Forrest et al. 1991; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996). Based on the collective evidence, the p.Ser349Pro 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
(Jan 28, 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: SCV001363423.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PAH c.1045T>C (p.Ser349Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded … (more)
Variant summary: PAH c.1045T>C (p.Ser349Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, 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. The variant allele was found at a frequency of 6.1e-05 in 276958 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.1045T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (se e.g. Bueno 2013, Couce 2013). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the most pronounced variant effect results in ~1% of normal activity (see e.g. Bueno 2013, Zurfluh 2008). Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Jun 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000239082.8
First in ClinVar: Jul 18, 2015 Last updated: Dec 19, 2017 |
Comment:
Functional studies reported that this variant is associated with enzyme activity at the limits of detection (Knappskog et al. 1995; Gjetting et al., 2001); In … (more)
Functional studies reported that this variant is associated with enzyme activity at the limits of detection (Knappskog et al. 1995; Gjetting et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as not responsive to BH4 therapy (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 22975760, 26666653, 27121329, 9450897, 29030855, 29749107, 30963030, 23500595, 17935162, 7860062, 24941924, 17924342, 28956315, 29288420, 30037505, 8095248, 2063869, 11161839, 25750018, 30375370, 1301193, 8659548, 8830172, 24705691, 22513348, 27535533, 21953985, 31589614) (less)
|
|
|
Pathogenic
(Jan 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Genetics and Molecular Pathology, SA Pathology
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002761792.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000629169.9
First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 349 of the PAH protein (p.Ser349Pro). … (more)
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 349 of the PAH protein (p.Ser349Pro). This variant is present in population databases (rs62508646, gnomAD 0.02%). This missense change has been observed in individuals with mild or classic phenylketonuria, atypical phenylketonuria and hyperphenylalaninemia (PMID: 2063869, 7860062, 8268925, 8659548, 9399896, 9781015, 10479481, 17096675, 17935162, 18294361, 23500595, 23514811). ClinVar contains an entry for this variant (Variation ID: 615). 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: 7860062, 8095248, 17935162, 23500595). This variant disrupts the p.Ser349 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16256386, 24705691, 26666653, 27264808). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Likely pathogenic
(Dec 20, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193874.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020 |
Comment:
NM_000277.1(PAH):c.1045T>C(S349P) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 8095248, 1301193, 21953985 … (more)
NM_000277.1(PAH):c.1045T>C(S349P) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 8095248, 1301193, 21953985 and 17935162. Classification of NM_000277.1(PAH):c.1045T>C(S349P) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
|
Pathogenic
(Sep 02, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611227.2
First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Mar 30, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201353.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
|
Pathogenic
(Jul 01, 1991)
|
no assertion criteria provided
Method: literature only
|
PHENYLKETONURIA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020787.65
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
See Forrest et al. (1991).
|
|
|
Pathogenic
(Sep 16, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV001463123.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
|
|
|
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: SCV000119302.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
Variant summary: PAH c.1045T>C (p.Ser349Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, 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. The variant allele was found at a frequency of 6.1e-05 in 276958 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.1045T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (se e.g. Bueno 2013, Couce 2013). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the most pronounced variant effect results in ~1% of normal activity (see e.g. Bueno 2013, Zurfluh 2008). Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Functional studies reported that this variant is associated with enzyme activity at the limits of detection (Knappskog et al. 1995; Gjetting et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as not responsive to BH4 therapy (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 22975760, 26666653, 27121329, 9450897, 29030855, 29749107, 30963030, 23500595, 17935162, 7860062, 24941924, 17924342, 28956315, 29288420, 30037505, 8095248, 2063869, 11161839, 25750018, 30375370, 1301193, 8659548, 8830172, 24705691, 22513348, 27535533, 21953985, 31589614)
Comment:
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 349 of the PAH protein (p.Ser349Pro). This variant is present in population databases (rs62508646, gnomAD 0.02%). This missense change has been observed in individuals with mild or classic phenylketonuria, atypical phenylketonuria and hyperphenylalaninemia (PMID: 2063869, 7860062, 8268925, 8659548, 9399896, 9781015, 10479481, 17096675, 17935162, 18294361, 23500595, 23514811). ClinVar contains an entry for this variant (Variation ID: 615). 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: 7860062, 8095248, 17935162, 23500595). This variant disrupts the p.Ser349 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16256386, 24705691, 26666653, 27264808). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
NM_000277.1(PAH):c.1045T>C(S349P) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 8095248, 1301193, 21953985 and 17935162. Classification of NM_000277.1(PAH):c.1045T>C(S349P) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
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:
Across a selection of the available literature, the PAH c.1045T>C (p.Ser349Pro) missense variant has been identified in a total of 41 individuals with phenylalanine hydroxylase deficiency, including in a homozygous state in four patients, in a compound heterozygous state in 39 patients, and in a heterozygous state in one patient (Forrest et al. 1991; John et al. 1992; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996; Vela-Amieva et al. 2015; Aldámiz-EchevarrÃa et al. 2016). The variant was also identified in an additional eight alleles of unknown zygosity (Zurflüh et al. 2008; Couce et al. 2013). The p.Ser349Pro variant was absent from 152 control individuals but is reported at an allele frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Ser349Pro variant is associated with a severe phenotype and results in significantly reduced PAH activity levels of between 0% and 1.2%, and immunoreactivity levels of between 0% and 2.0% compared to wild type (Forrest et al. 1991; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996). Based on the collective evidence, the p.Ser349Pro 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:
Variant summary: PAH c.1045T>C (p.Ser349Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, 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. The variant allele was found at a frequency of 6.1e-05 in 276958 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.1045T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (se e.g. Bueno 2013, Couce 2013). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the most pronounced variant effect results in ~1% of normal activity (see e.g. Bueno 2013, Zurfluh 2008). Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Functional studies reported that this variant is associated with enzyme activity at the limits of detection (Knappskog et al. 1995; Gjetting et al., 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Reported as not responsive to BH4 therapy (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 22975760, 26666653, 27121329, 9450897, 29030855, 29749107, 30963030, 23500595, 17935162, 7860062, 24941924, 17924342, 28956315, 29288420, 30037505, 8095248, 2063869, 11161839, 25750018, 30375370, 1301193, 8659548, 8830172, 24705691, 22513348, 27535533, 21953985, 31589614)
Comment:
This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 349 of the PAH protein (p.Ser349Pro). This variant is present in population databases (rs62508646, gnomAD 0.02%). This missense change has been observed in individuals with mild or classic phenylketonuria, atypical phenylketonuria and hyperphenylalaninemia (PMID: 2063869, 7860062, 8268925, 8659548, 9399896, 9781015, 10479481, 17096675, 17935162, 18294361, 23500595, 23514811). ClinVar contains an entry for this variant (Variation ID: 615). 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: 7860062, 8095248, 17935162, 23500595). This variant disrupts the p.Ser349 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16256386, 24705691, 26666653, 27264808). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
NM_000277.1(PAH):c.1045T>C(S349P) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 8095248, 1301193, 21953985 and 17935162. Classification of NM_000277.1(PAH):c.1045T>C(S349P) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| [Genotype and phenotype correlation of phenylalanine hydroxylase deficiency among patients from Henan]. | Zhao D | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2016 | PMID: 27264808 |
| Molecular epidemiology, genotype-phenotype correlation and BH4 responsiveness in Spanish patients with phenylketonuria. | Aldámiz-Echevarría L | Journal of human genetics | 2016 | PMID: 27121329 |
| 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 |
| Phenylalanine hydroxylase deficiency in Mexico: genotype-phenotype correlations, BH4 responsiveness and evidence of a founder effect. | Vela-Amieva M | Clinical genetics | 2015 | PMID: 24941924 |
| Mutation spectrum of six genes in Chinese phenylketonuria patients obtained through next-generation sequencing. | Gu Y | PloS one | 2014 | PMID: 24705691 |
| Molecular epidemiology and genotype-phenotype correlation in phenylketonuria patients from South Spain. | Bueno MA | Journal of human genetics | 2013 | PMID: 23514811 |
| Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain. | Couce ML | Gene | 2013 | PMID: 23500595 |
| Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene. | Groselj U | Molecular genetics and metabolism | 2012 | PMID: 22513348 |
| Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase. | Shi Z | Proteins | 2012 | PMID: 21953985 |
| A mutation analysis of the phenylalanine hydroxylase (PAH) gene in the Israeli population. | Bercovich D | Annals of human genetics | 2008 | PMID: 18294361 |
| Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Zurflüh MR | Human mutation | 2008 | PMID: 17935162 |
| Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: a 96% detection rate with ten novel mutations. | Daniele A | Annals of human genetics | 2007 | PMID: 17096675 |
| Phenylketonuria mutations in Northern China. | Song F | Molecular genetics and metabolism | 2005 | PMID: 16256386 |
| The mutant genotype is the main determinant of the metabolic phenotype in phenylalanine hydroxylase deficiency. | Bénit P | Molecular genetics and metabolism | 1999 | PMID: 10479481 |
| 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 |
| Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations. | Kayaalp E | American journal of human genetics | 1997 | PMID: 9399896 |
| PAH deficiency in Italy: correlation of genotype with phenotype in the Sicilian population. | Romano V | Journal of inherited metabolic disease | 1996 | PMID: 8830172 |
| 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 |
| The PKU mutation S349P causes complete loss of catalytic activity in the recombinant phenylalanine hydroxylase enzyme. | Knappskog PM | Human genetics | 1995 | PMID: 7860062 |
| Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. | Guldberg P | Human molecular genetics | 1993 | PMID: 8268925 |
| A missense mutation, S349P, completely inactivates phenylalanine hydroxylase in north African Jews with phenylketonuria. | Weinstein M | Human genetics | 1993 | PMID: 8095248 |
| Five mutations at the PAH locus account for almost 90% of PKU mutations in French-Canadians from eastern Quebec. | John SW | Human mutation | 1992 | PMID: 1301193 |
| Mutation detection in phenylketonuria by using chemical cleavage of mismatch: importance of using probes from both normal and patient samples. | Forrest SM | American journal of human genetics | 1991 | PMID: 2063869 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
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Text-mined citations for rs62508646 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
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Record last updated Nov 10, 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.
NCBI staff processed allelic variant 612349.0032 according to the nucleotide description in the paper by Forrest et al., 1991 (PubMed ), namely "..alteration was identified in exon 10 where the change from TCA to CCA at codon 349 altered the amino acid from serine to arginine...". Codon 349 is indeed TCA, but CCA encodes proline.