ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.1028A>G (p.Tyr343Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000277.3(PAH):c.1028A>G (p.Tyr343Cys)
Variation ID: 102477 Accession: VCV000102477.9
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 12q23.2 12: 102844373 (GRCh38) [ NCBI UCSC ] 12: 103238151 (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 Sep 5, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000277.3:c.1028A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Tyr343Cys missense NM_001354304.2:c.1028A>G NP_001341233.1:p.Tyr343Cys missense NC_000012.12:g.102844373T>C NC_000012.11:g.103238151T>C NG_008690.2:g.119038A>G P00439:p.Tyr343Cys - Protein change
- Y343C
- Other names
- -
- Canonical SPDI
- NC_000012.12:102844372:T:C
-
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
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. |
---|---|---|---|---|
Likely pathogenic (2) |
criteria provided, single submitter
|
Oct 1, 2015 | RCV000088708.1 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Sep 5, 2023 | RCV001194126.8 |
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. |
|
---|---|---|---|---|---|
Likely pathogenic
(Oct 01, 2015)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000582433.3
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
Comment:
The Y343C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is … (more)
The Y343C variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Y343C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants at the same residue (Y343D and Y343F) and in nearby residues (D388Y, I340T, K341/R/T, A342T/P, G344R/S/D/V, A345S/T, G346R/E, L347F, L348V) have been reported in the Human Gene Mutation Database in association with phenylketonuria (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret the Y343C variant to be likely pathogenic; however, the possibility that it is benign cannot be excluded. (less)
|
|
Pathogenic
(Sep 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004209601.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
|
|
Pathogenic
(Feb 04, 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: SCV001363416.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: PAH c.1028A>G (p.Tyr343Cys) results in a non-conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain of the encoded protein … (more)
Variant summary: PAH c.1028A>G (p.Tyr343Cys) results in a non-conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain 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 246022 control chromosomes (gnomAD). c.1028A>G has been reported in the literature in multiple compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, PKU). Based on the data provided by the BioPKU database, the variant was found in 7 patients with mild hyperphenylalaninaemia or mild PKU (Garbade 2018). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
Pathogenic
(Sep 05, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Phenylketonuria
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002245607.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 343 of the PAH protein … (more)
This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 343 of the PAH protein (p.Tyr343Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of phenylketonuria (PMID: 19913839, 23690520, 23842451, 32668217; BIOPKU http://www.biopku.org). ClinVar contains an entry for this variant (Variation ID: 102477). 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. For these reasons, this variant has been 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: SCV000119288.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
|
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 |
---|---|---|---|---|
The Genetic Landscape and Epidemiology of Phenylketonuria. | Hillert A | American journal of human genetics | 2020 | PMID: 32668217 |
Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria. | Garbade SF | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 29997390 |
Long-term treatment of phenylketonuria with a new medical food containing large neutral amino acids. | Concolino D | European journal of clinical nutrition | 2017 | PMID: 27623981 |
Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype. | Anjema K | Orphanet journal of rare diseases | 2013 | PMID: 23842451 |
Long-term follow-up and outcome of phenylketonuria patients on sapropterin: a retrospective study. | Keil S | Pediatrics | 2013 | PMID: 23690520 |
Unresponsiveness to tetrahydrobiopterin of phenylalanine hydroxylase deficiency. | Ponzone A | Metabolism: clinical and experimental | 2010 | PMID: 19913839 |
PAH gene mutations in the Sicilian population: association with minihaplotypes and expression analysis. | Mirisola MG | Molecular genetics and metabolism | 2001 | PMID: 11708866 |
http://www.biopku.org | - | - | - | - |
Text-mined citations for rs62507265 ...
HelpRecord 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.