ClinVar Genomic variation as it relates to human health
NM_000277.3(PAH):c.620A>G (p.Asn207Ser)
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
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NM_000277.3(PAH):c.620A>G (p.Asn207Ser)
Variation ID: 102765 Accession: VCV000102765.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12q23.2 12: 102855222 (GRCh38) [ NCBI UCSC ] 12: 103249000 (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 Mar 19, 2014 Feb 14, 2024 Jul 23, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000277.3:c.620A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000268.1:p.Asn207Ser missense NM_001354304.2:c.620A>G NP_001341233.1:p.Asn207Ser missense NC_000012.12:g.102855222T>C NC_000012.11:g.103249000T>C NG_008690.2:g.108189A>G P00439:p.Asn207Ser - Protein change
- N207S
- Other names
- NM_000277.3(PAH):c.620A>G
- Canonical SPDI
- NC_000012.12:102855221:T:C
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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PAH | - | - |
GRCh38 GRCh37 |
1485 | 1604 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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not provided (1) |
no classification provided
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- | RCV000089015.1 | |
Likely pathogenic (4) |
reviewed by expert panel
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Jul 23, 2023 | RCV000668775.11 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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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
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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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Likely pathogenic
(Jul 23, 2023)
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reviewed by expert panel
Method: curation
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Phenylketonuria
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen PAH Variant Curation Expert Panel
Accession: SCV004015309.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
The NM_000277.3:c.620A>G variant in PAH is a missense variant predicted to cause substitution of asparagine by serine at amino acid 207 (p.Asn207Ser). This variant has … (more)
The NM_000277.3:c.620A>G variant in PAH is a missense variant predicted to cause substitution of asparagine by serine at amino acid 207 (p.Asn207Ser). This variant has been detected in at least 5 unrelated individuals with PAH deficiency (PMID: 32668217, PMID: 9048935). Of these individuals, one was a compound heterozygote for the variant and a likely pathogenic variant, p.Pro281Leu, in trans (phase confirmed by parental testing) (PMID: 9048935), and four were compound heterozygotes for the variant and pathogenic variants, p.Ala300Ser, p.Ala403Val, p.Glu390Gly, p.Arg252Gln, in unknown phase (PMID: 32668217) (3pts total, PM3_Strong). One of these individuals had plasma phenylalanine >120 µmol/L without the exclusion of a defect of BH4 cofactor metabolism (PMID: 9048935) (PP4). This variant is absent in gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.77 which is above the threshold of 0.75, evidence that correlates with impact to PAH function (PP3). There is a ClinVar entry for this variant (Variation ID: 102765, 1 star review status) with one submitter classifying the variant as pathogenic, one submitter classifying the variant as likely pathogenic, and one submitter classifying the variant as a variant of uncertain significance. In summary, this variant meets the criteria to be classified as likely pathogenic for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting, PM3_Strong, PP3, PP4. (less)
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Pathogenic
(Mar 29, 2022)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001213212.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn207 amino acid residue in PAH. Other variant(s) that disrupt this … (more)
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn207 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9452061, 12554741). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 102765). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9048935, 17096675, 31332730). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 207 of the PAH protein (p.Asn207Ser). (less)
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Uncertain significance
(Aug 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000793428.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(Jul 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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Phenylketonuria
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV001810506.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
Sex: mixed
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not provided
(-)
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no classification provided
Method: not provided
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not provided
Affected status: not provided
Allele origin:
not provided
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DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE
Accession: SCV000119619.1
First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014 |
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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 |
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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 |
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 |
Deamidations in recombinant human phenylalanine hydroxylase. Identification of labile asparagine residues and functional characterization of Asn --> Asp mutant forms. | Carvalho RN | The Journal of biological chemistry | 2003 | PMID: 12554741 |
Identification of three novel mutations in Korean phenylketonuria patients: R53H, N207D, and Y325X. | Park YS | Human mutation | 1998 | PMID: 9452061 |
Two novel PAH gene mutations detected in Italian phenylketonuric patients. | Argiolas A | Human genetics | 1997 | PMID: 9048935 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/83be9c96-02b3-4161-ae5b-30bade6f25c3 | - | - | - | - |
Text-mined citations for rs62508721 ...
HelpRecord last updated Feb 14, 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.