This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 190 of the PAH protein (p.Val190Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related diseases (PMID: 9452062, 11486900, 17502162, 26666653; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102740). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. Experimental studies have shown that this missense change does not substantially affect PAH function (PMID: 15557004). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.569T>C (p.Val190Ala)
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.
(5)
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
5
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.569T>C (p.Val190Ala)
Variation ID: 102740 Accession: VCV000102740.6
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102855273 (GRCh38) [ NCBI UCSC ] 12: 103249051 (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 Feb 14, 2024 Oct 22, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.569T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Val190Ala missense NM_001354304.2:c.569T>C NP_001341233.1:p.Val190Ala missense NC_000012.12:g.102855273A>G NC_000012.11:g.103249051A>G NG_008690.2:g.108138T>C P00439:p.Val190Ala - Protein change
- V190A
- Other names
- -
- Canonical SPDI
- NC_000012.12:102855272: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- 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. |
|||
| 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. |
|---|---|---|---|---|
| not provided (1) |
no classification provided
|
- | RCV000088989.1 | |
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Oct 22, 2023 | RCV000632878.8 |
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
(Sep 08, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000754078.5
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 190 of the PAH protein (p.Val190Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 190 of the PAH protein (p.Val190Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related diseases (PMID: 9452062, 11486900, 17502162, 26666653; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102740). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. Experimental studies have shown that this missense change does not substantially affect PAH function (PMID: 15557004). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 22, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201350.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
|
Pathogenic
(Jan 11, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000788960.1
First in ClinVar: May 28, 2018 Last updated: May 28, 2018 |
|
|
|
Pathogenic
(May 25, 2020)
|
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: SCV001370579.1
First in ClinVar: Jul 16, 2020 Last updated: Jul 16, 2020 |
Comment:
Variant summary: PAH c.569T>C (p.Val190Ala) 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.569T>C (p.Val190Ala) 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 was absent in 251330 control chromosomes. c.569T>C has been reported in the literature among compound heterozygote genotypes in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Michiels_1998, Spaapen_2001, Dobrowlski_2007, Jeannesson-Thivisol_2015, Kuznetcova_2019, Quirk_2012). These data indicate that the variant is very likely to be associated with disease. Several publications report conflicting experimental evidence evaluating an impact on protein function (example, Erlandsen_2004, Zurfluh_2008, Himmelreich_2018). The most pronounced variant effect results in 30%-50% of normal activity (Himmelreich_2018). Two 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)
|
|
|
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: SCV000119593.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
Comment:
Comment:
Variant summary: PAH c.569T>C (p.Val190Ala) 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 was absent in 251330 control chromosomes. c.569T>C has been reported in the literature among compound heterozygote genotypes in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Michiels_1998, Spaapen_2001, Dobrowlski_2007, Jeannesson-Thivisol_2015, Kuznetcova_2019, Quirk_2012). These data indicate that the variant is very likely to be associated with disease. Several publications report conflicting experimental evidence evaluating an impact on protein function (example, Erlandsen_2004, Zurfluh_2008, Himmelreich_2018). The most pronounced variant effect results in 30%-50% of normal activity (Himmelreich_2018). Two 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.
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:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 190 of the PAH protein (p.Val190Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related diseases (PMID: 9452062, 11486900, 17502162, 26666653; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102740). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PAH protein function. Experimental studies have shown that this missense change does not substantially affect PAH function (PMID: 15557004). For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: PAH c.569T>C (p.Val190Ala) 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 was absent in 251330 control chromosomes. c.569T>C has been reported in the literature among compound heterozygote genotypes in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Michiels_1998, Spaapen_2001, Dobrowlski_2007, Jeannesson-Thivisol_2015, Kuznetcova_2019, Quirk_2012). These data indicate that the variant is very likely to be associated with disease. Several publications report conflicting experimental evidence evaluating an impact on protein function (example, Erlandsen_2004, Zurfluh_2008, Himmelreich_2018). The most pronounced variant effect results in 30%-50% of normal activity (Himmelreich_2018). Two 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria. | Himmelreich N | Molecular genetics and metabolism | 2018 | PMID: 30037505 |
| 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 |
| Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype. | Anjema K | Orphanet journal of rare diseases | 2013 | PMID: 23842451 |
| Hyperphenylalaninemia in the Czech Republic: genotype-phenotype correlations and in silico analysis of novel missense mutations. | Réblová K | Clinica chimica acta; international journal of clinical chemistry | 2013 | PMID: 23357515 |
| Utility of phenylalanine hydroxylase genotype for tetrahydrobiopterin responsiveness classification in patients with phenylketonuria. | Quirk ME | Molecular genetics and metabolism | 2012 | PMID: 22841515 |
| 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 |
| START, a double blind, placebo-controlled pharmacogenetic test of responsiveness to sapropterin dihydrochloride in phenylketonuria patients. | Utz JR | Molecular genetics and metabolism | 2012 | PMID: 22112818 |
| Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Zurflüh MR | Human mutation | 2008 | PMID: 17935162 |
| Mutations in the phenylalanine hydroxylase gene identified in 95 patients with phenylketonuria using novel systems of mutation scanning and specific genotyping based upon thermal melt profiles. | Dobrowolski SF | Molecular genetics and metabolism | 2007 | PMID: 17502162 |
| Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations. | Erlandsen H | Proceedings of the National Academy of Sciences of the United States of America | 2004 | PMID: 15557004 |
| Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates. | Spaapen LJ | Journal of inherited metabolic disease | 2001 | PMID: 11486900 |
| Phenylketonuria and hyperphenylalaninemia in eastern Germany: a characteristic molecular profile and 15 novel mutations. | Hennermann JB | Human mutation | 2000 | PMID: 10679941 |
| Identification of seven new mutations in the phenylalanine hydroxylase gene, associated with hyperphenylalaninemia in the Belgian population. | Michiels L | Human mutation | 1998 | PMID: 9452062 |
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Text-mined citations for rs62514919 ...
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 Sep 29, 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.