VCV000102586.13 - ClinVar

NM_000277.3(PAH):c.1301C>A (p.Ala434Asp)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

6 submitters

2 conditions

Reviewed by expert panel

Pathogenic

Dec 2023 by ClinGen PAH Va… FDA Recognized Database

for Phenylketonuria

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000277.3(PAH):c.1301C>A (p.Ala434Asp)

Variation ID: 102586 Accession: VCV000102586.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102840414 (GRCh38) [ NCBI UCSC ] 12: 103234192 (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	Jun 17, 2024	Dec 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.1301C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Ala434Asp	missense
NM_001354304.2:c.1301C>A	NP_001341233.1:p.Ala434Asp	missense
NC_000012.12:g.102840414G>T
NC_000012.11:g.103234192G>T
NG_008690.2:g.122997C>A

... more HGVS ... less HGVS

Protein change

A434D

Other names

NM_000277.2(PAH):c.1301C>A
p.Ala434Asp

Canonical SPDI

NC_000012.12:102840413:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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) 0.00003

Links

ClinGen: CA229427 dbSNP: rs199475659 VarSome

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
Gene	OMIM	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	not provided (1)	no classification provided	-	RCV000088825.1
Phenylketonuria	Pathogenic (5)	reviewed by expert panel	Dec 30, 2023	RCV000169393.13

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 (Dec 30, 2023)	reviewed by expert panel (ClinGen PAH ACMG Specifications v1) Method: curation	Phenylketonuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen PAH Variant Curation Expert Panel FDA Recognized Database Accession: SCV004222613.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (3) PubMed: 21147011‚ 16256386‚ 18247293 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d30a56d8-d14c-492c-afea-2eaecad4b3f1 Comment: The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent … (more) The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID: 18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID: 16256386); p.E390G, p.R261Q (PMID: 21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID: 23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3. (less)
Likely pathogenic (Oct 13, 2014)	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015)) Method: literature only	Phenylketonuria (Autosomal recessive inheritance) Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000220785.2 First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022	Publications: PubMed (8) PubMed: 24401910‚ 18247293‚ 16256386‚ 19147918‚ 17924342‚ 21811977‚ 19099685‚ 23932990
Pathogenic (Jan 08, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001579238.3 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 16256386‚ 18247293‚ 24401910‚ 27264808‚ 29499199‚ 30037505 Comment: This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 434 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 434 of the PAH protein (p.Ala434Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 16256386, 18247293, 24401910, 27264808, 29499199). ClinVar contains an entry for this variant (Variation ID: 102586). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 30037505). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Nov 10, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004209615.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jul 29, 2021)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088616.1 First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022
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: SCV000119416.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014

Comment:

The c.1301C>A (p.Ala434Asp) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). PMID: 16256386, 21147011). This variant is absent in population databases. Residual enzyme activity of the p.A434D mutant is 21.7% of wild type, and the formation and stability of the PAH protein was affected (PMID: 18247293). This variant was detected with pathogenic variants: p.R252Q, p.R243Q (PMID: 16256386); p.E390G, p.R261Q (PMID: 21147011); p.R243Q (3 patients); IVS4-1G>A (2 patients); p.E280K, p.R111X (PMID: 23932990). Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PP4_Moderate, PS3_supporting, PM2_supporting, PP3.

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 434 of the PAH protein (p.Ala434Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with phenylketonuria (PMID: 16256386, 18247293, 24401910, 27264808, 29499199). ClinVar contains an entry for this variant (Variation ID: 102586). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 30037505). For these reasons, this variant has been 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Relationship between genotype, phenylalanine hydroxylase expression and in vitro activity and metabolic phenotype in phenylketonuria.	Himmelreich N	Molecular genetics and metabolism	2018	PMID: 30037505
Mutation spectrum of hyperphenylalaninemia candidate genes and the genotype-phenotype correlation in the Chinese population.	Wang R	Clinica chimica acta; international journal of clinical chemistry	2018	PMID: 29499199
[Genotype and phenotype correlation of phenylalanine hydroxylase deficiency among patients from Henan].	Zhao D	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2016	PMID: 27264808
The mutation spectrum of the phenylalanine hydroxylase (PAH) gene and associated haplotypes reveal ethnic heterogeneity in the Taiwanese population.	Liang Y	Journal of human genetics	2014	PMID: 24401910
Variations in genotype-phenotype correlations in phenylalanine hydroxylase deficiency in Chinese Han population.	Zhu T	Gene	2013	PMID: 23932990
[Study on the mutations of phenylalanine hydroxylase gene in patients with phenylketonuria in Shanxi province].	Gao WH	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2011	PMID: 21811977
Molecular genetics and impact of residual in vitro phenylalanine hydroxylase activity on tetrahydrobiopterin responsiveness in Turkish PKU population.	Dobrowolski SF	Molecular genetics and metabolism	2011	PMID: 21147011
Mutation characteristics of the PAH gene in four nationality groups in Xinjiang of China.	Yu WZ	Journal of genetics	2008	PMID: 19147918
[Spectrum of phenylalanine hydroxylase gene mutations and genotype-phenotype correlation in the patients with phenylketonuria in Beijing area of China].	Qu YJ	Zhonghua er ke za zhi = Chinese journal of pediatrics	2008	PMID: 19099685
[In vitro expression and structural analysis of four missense mutations (G247S, E280G, P362T, A434D) of phenylalanine hydroxylase gene].	Song F	Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics	2008	PMID: 18247293
Predicted effects of missense mutations on native-state stability account for phenotypic outcome in phenylketonuria, a paradigm of misfolding diseases.	Pey AL	American journal of human genetics	2007	PMID: 17924342
Phenylketonuria mutations in Northern China.	Song F	Molecular genetics and metabolism	2005	PMID: 16256386
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d30a56d8-d14c-492c-afea-2eaecad4b3f1	-	-	-	-
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Text-mined citations for rs199475659 ...

These 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

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.1301C>A (p.Ala434Asp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199475659 ...