This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the PAH protein (p.Pro211Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic phenylketonuria and PAH deficiency (PMID: 24350308; Invitae). ClinVar contains an entry for this variant (Variation ID: 120283). 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%. This variant disrupts the p.Pro211 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8268925, 9429153, 11708866, 16198137, 17935162, 23500595). 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.
ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.632C>T (p.Pro211Leu)
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.
(6)
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
6
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.632C>T (p.Pro211Leu)
Variation ID: 120283 Accession: VCV000120283.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102855210 (GRCh38) [ NCBI UCSC ] 12: 103248988 (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 Apr 1, 2014 Feb 20, 2024 Jan 25, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000277.3:c.632C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Pro211Leu missense NM_001354304.2:c.632C>T NP_001341233.1:p.Pro211Leu missense NC_000012.12:g.102855210G>A NC_000012.11:g.103248988G>A NG_008690.2:g.108201C>T - Protein change
- P211L
- Other names
- -
- Canonical SPDI
- NC_000012.12:102855209: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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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Jan 25, 2024 | RCV000106364.16 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
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Pathogenic
(Jan 25, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000629204.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the PAH protein (p.Pro211Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the PAH protein (p.Pro211Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic phenylketonuria and PAH deficiency (PMID: 24350308; Invitae). ClinVar contains an entry for this variant (Variation ID: 120283). 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%. This variant disrupts the p.Pro211 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8268925, 9429153, 11708866, 16198137, 17935162, 23500595). 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
(Sep 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209583.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
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Likely pathogenic
(Mar 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000798689.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
|
|
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Likely pathogenic
(Oct 17, 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: SCV001361332.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PAH c.632C>T (p.Pro211Leu) results in a non-conservative amino acid change in the catalytic domain (IPR041912) of the encoded protein sequence. Five of five … (more)
Variant summary: PAH c.632C>T (p.Pro211Leu) results in a non-conservative amino acid change in the catalytic domain (IPR041912) 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 251336 control chromosomes (gnomAD). c.632C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Gundorova_2016, Bik-Multanowski_2013). These data indicate that the variant may be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. In addition, another variant affecting the same codon, P211T, along with variants nearby, N207S, L213P, E214G, have been reported to be associated with PKU. Therefore, suggesting the region is important for protein function. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
|
|
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Likely pathogenic
(Jul 13, 2020)
|
no assertion criteria provided
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002088654.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
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probable-pathogenic
(-)
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no assertion criteria provided
Method: not provided
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Phenylketonuria
Affected status: not provided
Allele origin:
unknown
|
Inserm U 954, Faculté de Médecine de Nancy
Accession: SCV000143864.1
First in ClinVar: Apr 01, 2014 Last updated: Apr 01, 2014
Comment:
PKU patient
|
Comment:
Converted during submission to Likely pathogenic.
|
Comment:
Comment:
Variant summary: PAH c.632C>T (p.Pro211Leu) results in a non-conservative amino acid change in the catalytic domain (IPR041912) 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 251336 control chromosomes (gnomAD). c.632C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Gundorova_2016, Bik-Multanowski_2013). These data indicate that the variant may be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. In addition, another variant affecting the same codon, P211T, along with variants nearby, N207S, L213P, E214G, have been reported to be associated with PKU. Therefore, suggesting the region is important for protein function. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Converted during submission to Likely 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 211 of the PAH protein (p.Pro211Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with classic phenylketonuria and PAH deficiency (PMID: 24350308; Invitae). ClinVar contains an entry for this variant (Variation ID: 120283). 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%. This variant disrupts the p.Pro211 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8268925, 9429153, 11708866, 16198137, 17935162, 23500595). 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:
Variant summary: PAH c.632C>T (p.Pro211Leu) results in a non-conservative amino acid change in the catalytic domain (IPR041912) 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 251336 control chromosomes (gnomAD). c.632C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Gundorova_2016, Bik-Multanowski_2013). These data indicate that the variant may be associated with disease. Two ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic. In addition, another variant affecting the same codon, P211T, along with variants nearby, N207S, L213P, E214G, have been reported to be associated with PKU. Therefore, suggesting the region is important for protein function. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Comment:
Converted during submission to Likely pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Molecular genetics of PKU in Poland and potential impact of mutations on BH4 responsiveness. | Bik-Multanowski M | Acta biochimica Polonica | 2013 | PMID: 24350308 |
| Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain. | Couce ML | Gene | 2013 | PMID: 23500595 |
| Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Zurflüh MR | Human mutation | 2008 | PMID: 17935162 |
| Incidence of BH4-responsiveness in phenylalanine-hydroxylase-deficient Italian patients. | Fiori L | Molecular genetics and metabolism | 2005 | PMID: 16198137 |
| PAH gene mutations in the Sicilian population: association with minihaplotypes and expression analysis. | Mirisola MG | Molecular genetics and metabolism | 2001 | PMID: 11708866 |
| Molecular basis of mild hyperphenylalaninaemia in Poland. | Zekanowski C | Journal of medical genetics | 1997 | PMID: 9429153 |
| Mutational spectrum of phenylalanine hydroxylase deficiency in Sicily: implications for diagnosis of hyperphenylalaninemia in southern Europe. | Guldberg P | Human molecular genetics | 1993 | PMID: 8268925 |
Text-mined citations for rs281865443 ...
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.