ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.311C>A (p.Ala104Asp)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.311C>A (p.Ala104Asp)
Variation ID: 102650 Accession: VCV000102650.32
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102894776 (GRCh38) [ NCBI UCSC ] 12: 103288554 (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 Oct 8, 2024 Aug 7, 2018 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000277.3:c.311C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Ala104Asp missense NM_001354304.2:c.311C>A NP_001341233.1:p.Ala104Asp missense NC_000012.12:g.102894776G>T NC_000012.11:g.103288554G>T NG_008690.2:g.68635C>A P00439:p.Ala104Asp - Protein change
- A104D
- Other names
- NM_000277.2(PAH):c.311C>A
- Canonical SPDI
- NC_000012.12:102894775:G:T
-
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.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00005
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00004
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 |
1504 | 1627 |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 26, 2024 | RCV000088896.12 | |
Pathogenic (9) |
reviewed by expert panel
|
Aug 7, 2018 | RCV000349567.25 | |
PAH-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jan 2, 2024 | RCV003915115.3 |
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
(Aug 07, 2018)
|
reviewed by expert panel
Method: curation
|
Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen PAH Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV000852162.4 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
Comment:
PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency: 0.00009 in gnomAD; PS3: 26% PAH enzyme activity; PM3_Strong: Detected with Y414C, pathogenic in ClinVar and V245L … (more)
PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency: 0.00009 in gnomAD; PS3: 26% PAH enzyme activity; PM3_Strong: Detected with Y414C, pathogenic in ClinVar and V245L (P/LP) (PMID:9429153; PMID:24368688). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PS3, PM3_Strong). (less)
|
|
Pathogenic
(Jan 11, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000914557.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
Across a selection of the available literature, the PAH c.311C>A (p.Ala104Asp) missense variant has been identified in at least 12 individuals with phenylalanine hydroxylase deficiency … (more)
Across a selection of the available literature, the PAH c.311C>A (p.Ala104Asp) missense variant has been identified in at least 12 individuals with phenylalanine hydroxylase deficiency (PAH), including in one in a homozygous state, and in 11 in a compound heterozygous state (Guldberg et al. 1995; Zekanowski et al. 1997; Pronina et al. 2003; Ho et al. 2014; Trunzo et al. 2015). The p.Ala104Asp variant is associated with a mild phenotype with the exception of one compound heterozygous individual who presented with the classical form. Control data are unavailable for this variant, which is reported at a frequency of 0.000089 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrated that the p.Ala104Asp PAH retained 26% of its activity but with a significantly reduced half-life of the aggregates compared to wild type PAH. In vitro, wild type PAH was comprised of tetramers and dimers, whereas mutant PAH was primarily dimeric with moderate amounts of aggregates, and significantly reduced amounts of tetramers (Waters et al. 1998). Additionally, hybrid expression models have shown a modest decrease in reporter activity as well as an increase in the rate of degradation in homomeric interactions for the p.Ala104Asp mutant as compared to wildtype (Waters et al. 2001). Based on the collective evidence, the p.Ala104Asp 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
(May 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002800918.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
Pathogenic
(Jul 15, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002016507.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
Pathogenic
(Mar 28, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004201382.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Apr 07, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000330985.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
|
|
Pathogenic
(Aug 27, 2018)
|
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: SCV000919919.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: PAH c.311C>A (p.Ala104Asp) results in a non-conservative amino acid change located in the ACT domain of the encoded protein sequence. Three of five … (more)
Variant summary: PAH c.311C>A (p.Ala104Asp) results in a non-conservative amino acid change located in the ACT domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 246214 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (5.3e-05 vs 0.0079), allowing no conclusion about variant significance. c.311C>A has been reported in the literature in multiple individuals affected with mild PKU due to Phenylalanine Hydroxylase Deficiency (mild Phenylketonuria)(Zurfluh_2008, Bayat_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal activity. Two ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Dec 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000830766.7
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 104 of the PAH protein … (more)
This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 104 of the PAH protein (p.Ala104Asp). This variant is present in population databases (rs62642929, gnomAD 0.009%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 18299955, 22112818, 22526846, 23764561, 26666653). ClinVar contains an entry for this variant (Variation ID: 102650). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Pathogenic
(Feb 01, 2024)
|
criteria provided, single submitter
Method: curation
|
Phenylketonuria
Affected status: no
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051913.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
|
|
Pathogenic
(Jun 26, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000617703.4
First in ClinVar: Dec 19, 2017 Last updated: Sep 29, 2024 |
Comment:
Reported previously in the heterozygous state, in the presence of a second PAH variant, in association with phenylketonuria (PKU) (PMID: 1301187, 9429153, 12655551, 17627389, 24368688); … (more)
Reported previously in the heterozygous state, in the presence of a second PAH variant, in association with phenylketonuria (PKU) (PMID: 1301187, 9429153, 12655551, 17627389, 24368688); Published functional studies found this variant is associated with reduced protein expression and catalytic activity (PMID: 9191407, 21953985); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Associated with tetrahydrobiopterin (BH4) responsiveness (PMID: 17935162); This variant is associated with the following publications: (PMID: 11461190, 10384369, 9792411, 22526846, 9429153, 24368688, 17627389, 23357515, 12655551, 30037505, 30648773, 31355225, 22112818, 18299955, 23764561, 26666653, 26542770, 23514811, 34426522, 32668217, 33101986, 32778825, 9191407, 1301187, 17935162, 21953985) (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001927449.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743459.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
Pathogenic
(Jun 21, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002088669.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
Pathogenic
(Jan 02, 2024)
|
no assertion criteria provided
Method: clinical testing
|
PAH-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004733016.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The PAH c.311C>A variant is predicted to result in the amino acid substitution p.Ala104Asp. This variant has been reported in the homozygous state or with … (more)
The PAH c.311C>A variant is predicted to result in the amino acid substitution p.Ala104Asp. This variant has been reported in the homozygous state or with a second PAH variant in patients with phenylalanine hydroxylase deficiency, ranging from mild hyperphenylalaninemia to classic phenylketonuria (PKU) (e.g., Zekanowski et al. 1997. PubMed ID: 9429153; Bercovich et al. 2008. PubMed ID: 18299955; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653; Trunzo et al. 2015. PubMed ID: 26210745; Su et al. 2019. PubMed ID: 31355225; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). Based on functional studies, the p.Ala104Asp amino acid change has been reported to result in reduced PAH enzyme activity and has been classified as a BH4-responsive amino acid substitution (Zurflüh et al. 2008. PubMed ID: 17935162; Shi et al. 2012. PubMed ID: 21953985; Himmelreich et al. 2018. PubMed ID: 30037505). This variant is reported in 0.014% of alleles in individuals of European (Finnish) descent in gnomAD. It has been classified as pathogenic by multiple outside laboratories as well as the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/102650/). Based on these observations, we classify this variant 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: SCV000119494.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
|
click to load more click to collapse |
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 |
---|---|---|---|---|
Mutational and phenotypical spectrum of phenylalanine hydroxylase deficiency in Denmark. | Bayat A | Clinical genetics | 2016 | PMID: 26542770 |
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 south Italy: Genotype-phenotype correlations, identification of a novel mutant PAH allele and prediction of BH4 responsiveness. | Trunzo R | Clinica chimica acta; international journal of clinical chemistry | 2015 | PMID: 26210745 |
The Molecular Bases of Phenylketonuria (PKU) in New South Wales, Australia: Mutation Profile and Correlation with Tetrahydrobiopterin (BH4) Responsiveness. | Ho G | JIMD reports | 2014 | PMID: 24368688 |
Phenylalanine hydroxylase deficiency in the Slovak population: genotype-phenotype correlations and genotype-based predictions of BH4-responsiveness. | Polak E | Gene | 2013 | PMID: 23764561 |
Prevalence of tetrahydrobiopterine (BH4)-responsive alleles among Austrian patients with PAH deficiency: comprehensive results from molecular analysis in 147 patients. | Sterl E | Journal of inherited metabolic disease | 2013 | PMID: 22526846 |
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 |
Genotype-phenotype correlations analysis of mutations in the phenylalanine hydroxylase (PAH) gene. | Bercovich D | Journal of human genetics | 2008 | PMID: 18299955 |
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. | Zurflüh MR | Human mutation | 2008 | PMID: 17935162 |
The molecular basis of phenylketonuria in Latvia. | Pronina N | Human mutation | 2003 | PMID: 12655551 |
Homomeric and heteromeric interactions between wild-type and mutant phenylalanine hydroxylase subunits: evaluation of two-hybrid approaches for functional analysis of mutations causing hyperphenylalaninemia. | Waters PJ | Molecular genetics and metabolism | 2001 | PMID: 11461190 |
Mutations in exon 3 of the PAH gene causing mild hyperphenylalaninemia. | Zekanowski C | Genetic testing | 1999 | PMID: 10495930 |
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 |
Molecular basis of mild hyperphenylalaninaemia in Poland. | Zekanowski C | Journal of medical genetics | 1997 | PMID: 9429153 |
In vivo assessment of mutations in the phenylalanine hydroxylase gene by phenylalanine loading: characterization of seven common mutations. | Guldberg P | European journal of pediatrics | 1995 | PMID: 7556322 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH | - | - | - | - |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/86ce59a8-cc5a-46f9-9b96-2254638db653 | - | - | - | - |
click to load more click to collapse |
Text-mined citations for rs62642929 ...
HelpRecord last updated Oct 13, 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.