VCV000000580.105 - ClinVar

NM_000277.3(PAH):c.838G>A (p.Glu280Lys)

Germline

Classification

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.

(19)

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

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.838G>A (p.Glu280Lys)

Variation ID: 580 Accession: VCV000000580.105

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102852819 (GRCh38) [ NCBI UCSC ] 12: 103246597 (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	Mar 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.838G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Glu280Lys	missense
NM_001354304.2:c.838G>A	NP_001341233.1:p.Glu280Lys	missense
NC_000012.12:g.102852819C>T
NC_000012.11:g.103246597C>T
NG_008690.2:g.110592G>A
	P00439:p.Glu280Lys

... more HGVS ... less HGVS

Protein change

E280K

Other names

p.E280K:GAA>AAA
p.E280K

Canonical SPDI

NC_000012.12:102852818:C: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.

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD) 0.00009

Trans-Omics for Precision Medicine (TOPMed) 0.00015

Links

ClinGen: CA251525 UniProtKB: P00439#VAR_000980 OMIM: 612349.0004 dbSNP: rs62508698 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.
Phenylketonuria	Pathogenic (11)	criteria provided, multiple submitters, no conflicts	Mar 25, 2024	RCV000000610.98
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 31, 2020	RCV000078532.27
Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis	Pathogenic (1)	no assertion criteria provided	Oct 27, 2022	RCV003162201.8
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jul 29, 2020	RCV002512608.9
PAH-related disorder	Pathogenic (1)	no assertion criteria provided	Mar 6, 2024	RCV004739272.1

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 (Mar 02, 2017)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110388.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Publications: PubMed (2) PubMed: 23500595‚ 2564729 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH http://www.pahdb.mcgill.ca/ http://www.pahdb.mcgill.ca/ Number of individuals with the variant: 21 Sex: mixed
Pathogenic (Feb 15, 2018)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000917919.1 First in ClinVar: May 31, 2019 Last updated: May 31, 2019	Publications: PubMed (2) PubMed: 23500595‚ 9399896 Comment: Variant summary: PAH c.838G>A (p.Glu280Lys) results in a conservative amino acid change located in the C-terminal domain of the Aromatic amino acid hydroxylase (IPR019774) of … (more) Variant summary: PAH c.838G>A (p.Glu280Lys) results in a conservative amino acid change located in the C-terminal domain of the Aromatic amino acid hydroxylase (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The c.838G>A variant has been reported in the literature in several individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) either in a homozygous state or in a compound heterozygosity with other HPA variants considered as pathogenic (e.g. Pey 2003, Kayaalp 1997, Couce 2013, Aldamiz-Echevarria 2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the variant affected both folding and catalysis (Pey 2003). The most pronounced variant effect results in <10% of normal activity. One study reported absent/minimal BH4 responsiveness for patients carrying the variant (Couce 2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Dec 19, 2019)	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019)) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV001193931.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (7) PubMed: 12655546‚ 11524738‚ 9781015‚ 17935162‚ 1971144‚ 23500595‚ 2564729 Comment: NM_000277.1(PAH):c.838G>A(E280K) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 12655546, 11524738, 9781015, 17935162, 1971144, … (more) NM_000277.1(PAH):c.838G>A(E280K) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 12655546, 11524738, 9781015, 17935162, 1971144, 23500595 and 2564729. Classification of NM_000277.1(PAH):c.838G>A(E280K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
Pathogenic (Aug 31, 2020)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000888355.4 First in ClinVar: Mar 13, 2019 Last updated: Dec 31, 2022	Publications: PubMed (8) PubMed: 2564729‚ 23500595‚ 2014036‚ 12655546‚ 17935162‚ 22763404‚ 30963030‚ 29499199 Comment: This variant was found in at least one symptomatic individual and predicted to have a damaging effect on the protein. The variant occurs in multiple … (more) This variant was found in at least one symptomatic individual and predicted to have a damaging effect on the protein. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. It has also been reported to be associated with classic PKU and undetectable PAH enzyme activity (PMID: 12655546 (2003), 22763404(2012), 23500595 (2013), and 30963030 (2019)). (less)
Pathogenic (May 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016471.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Jul 29, 2020)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV003651402.2 First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024	Publications: PubMed (6) PubMed: 2014036‚ 2564729‚ 12655546‚ 17935162‚ 21953985‚ 31355225 Comment: The alteration results in an amino acid change:_x000D_ _x000D_ The c.838G>A (p.E280K) alteration is located in coding exon 7 of the PAH gene. This alteration … (more) The alteration results in an amino acid change:_x000D_ _x000D_ The c.838G>A (p.E280K) alteration is located in coding exon 7 of the PAH gene. This alteration results from a G to A substitution at nucleotide position 838, causing the glutamic acid (E) at amino acid position 280 to be replaced by a lysine (K). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the PAH c.838G>A alteration was observed in 0.006% (16/282,678) of total alleles studied, with a frequency of 0.008% (10/128,998) in the European (non-Finnish) subpopulation. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported homozygous or compound heterozygous with another mutation in PAH in multiple unrelated patients with phenylalanine hydroxylase (PAH) deficiency (Lyonnet, 1989; Okano, 1991; Su, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.E280 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis demonstrated that the E280K alteration decreases PAH activity significantly compared to wild-type (Zurflüh, 2008; Shi, 2012). Three-dimensional structural analysis of the protein reveals that this alteration is an active site mutation (Pey, 2003). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.E280K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Oct 08, 2014)	criteria provided, single submitter (ACGS Guidelines, 2013) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Study: VKGL Data-share Consensus Accession: SCV000744094.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	3billion Accession: SCV002572790.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). It is located in a mutational hot … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000580). The variant is in trans with the other variant. Different missense changes at the same codon (p.Glu280Gln, p.Glu280Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102864 , VCV000102866). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Global developmental delay (present)
Pathogenic (May 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611235.2 First in ClinVar: Oct 23, 2016 Last updated: Dec 31, 2022
Pathogenic (Jan 28, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000239076.15 First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023	Comment: Published functional studies demonstrate that E280K is associated no detectable residual enzyme activity (Pey et al., 2003; Pey et al., 2007); Not observed at a … (more) Published functional studies demonstrate that E280K is associated no detectable residual enzyme activity (Pey et al., 2003; Pey et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 2014036, 21953985, 30747360, 9399896, 1971144, 25087612, 22975760, 23500595, 17935162, 25750018, 2564729, 28676969, 29499199, 29317692, 12655546, 9101291, 30037505, 30963030, 31355225, 31589614, 33101986, 17924342, 32778825, 29288420, 33375644) (less)
Pathogenic (Jan 16, 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: SCV000629219.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024	Publications: PubMed (7) PubMed: 28492532‚ 2014036‚ 2564729‚ 12655546‚ 17935162‚ 23500595‚ 21953985 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 280 of the PAH protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 280 of the PAH protein (p.Glu280Lys). This variant is present in population databases (rs62508698, gnomAD 0.008%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 2014036, 2564729, 12655546, 17935162, 23500595). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 580). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 2014036, 12655546, 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 25, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201348.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Nov 09, 2016)	no assertion criteria provided (ACGS Guidelines, 2013) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV000746008.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453100.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Pathogenic (Jan 01, 1997)	no assertion criteria provided Method: literature only	PHENYLKETONURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020760.68 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 1971144‚ 9101291 Lyonnet, S., Caillaud, C., Rey, F., (more...) Lyonnet, S., Caillaud, C., Rey, F., Berthelon, M., Frezal, J., Rey, J., Munnich, A. Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency. Am. J. Hum. Genet. 44: 511-517, 1989. Comment on evidence: Lyonnet et al. (1989) found a change of glu280-to-lys (E280K) in a child with a variant form of phenylketonuria (PKU; 261600). The enzyme showed partial … (more) Lyonnet et al. (1989) found a change of glu280-to-lys (E280K) in a child with a variant form of phenylketonuria (PKU; 261600). The enzyme showed partial residual activity. The mutation was linked to a rare RFLP haplotype at the PAH locus found in South Europe and North Africa. In studies to the time of publication, the genotype-haplotype association was both inclusive and exclusive. Okano et al. (1990) demonstrated the E280K mutation in association with haplotype 1 in a patient in Denmark. Lyonnet et al. (1989) found this mutation in association with haplotype 38, representing about 10% of all PKU alleles in North Africa. Okano et al. (1990) suggested that this was a recurrent mutation. The site of the mutation involves a CpG dinucleotide. From analysis of the PAH mutation database, Byck et al. (1997) demonstrated that the E280K allele accounts for 1.5% of PKU chromosomes worldwide. It occurs on 4 different haplotypes in Europeans and on haplotypes 1 and 2 in Quebec. Whereas a single recombination event could explain the 2 haplotype associations in Quebec, the mutation involves a CpG dinucleotide, a recognized mutation hotspot. By analyzing multiallelic markers 5-prime and 3-prime to the E280K allele on 12 mutant and 30 normal chromosomes, Byck et al. (1997) concluded that recurrent mutation is the likely origin of E280K in Quebec. Byck et al. (1997) found 48 CpG sites (sense and antisense strands) in the PAH gene. Of these, 7 were devoid of known mutations, 16 harbored 'PKU' alleles involving CpG doublets, and the remainder contained mutations that did not involve a C-to-T or G-to-A substitution in the doublet. These hypermutable CpG sites were found to harbor 32 different mutations in association with at least 66 different haplotypes and resulting hyperphenylalaninemia. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952548.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Oct 27, 2022)	no assertion criteria provided Method: clinical testing	Polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis Affected status: yes Allele origin: paternal	Undiagnosed Diseases Network, NIH Accession: SCV003915642.1 First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023	Number of individuals with the variant: 1 Clinical Features: Hyperphenylalaninemia (present) Age: 0-9 years Sex: male Tissue: Blood
Pathogenic (Mar 06, 2024)	no assertion criteria provided Method: clinical testing	PAH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005362913.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The PAH c.838G>A variant is predicted to result in the amino acid substitution p.Glu280Lys. This is a commonly reported pathogenic variant that, in the homozygous … (more) The PAH c.838G>A variant is predicted to result in the amino acid substitution p.Glu280Lys. This is a commonly reported pathogenic variant that, in the homozygous state, has been associated with classic phenylketonuria (PKU) (e.g., Couce et al. 2013. PubMed ID: 23500595; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The p.Glu280 amino acid has been reported to be located in the active site, and in functional assays the p.Glu280Lys substitution has essentially abolished PAH enzyme activity and resulted in a PAH protein that is non-responsive to BH4 (e.g., Pey et al. 2003. PubMed ID: 12655546; Zurflüh et al. 2008. PubMed ID: 17935162). Different substitutions of the same amino acid (p.Glu280Ala, p.Glu280Gly) have also been reported to be causative for phenylalanine hydroxylase deficiency (e.g., Aulehla-Scholz and Heilbronner. 2003. PubMed ID: 12655553; Song et al. 2005. PubMed ID: 16256386). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Multiple independent submitters to ClinVar have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/580). In summary, this variant is interpreted 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: SCV000119733.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014
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Comment:

Variant summary: PAH c.838G>A (p.Glu280Lys) results in a conservative amino acid change located in the C-terminal domain of the Aromatic amino acid hydroxylase (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The c.838G>A variant has been reported in the literature in several individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) either in a homozygous state or in a compound heterozygosity with other HPA variants considered as pathogenic (e.g. Pey 2003, Kayaalp 1997, Couce 2013, Aldamiz-Echevarria 2016). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the variant affected both folding and catalysis (Pey 2003). The most pronounced variant effect results in <10% of normal activity. One study reported absent/minimal BH4 responsiveness for patients carrying the variant (Couce 2013). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

NM_000277.1(PAH):c.838G>A(E280K) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 12655546, 11524738, 9781015, 17935162, 1971144, 23500595 and 2564729. Classification of NM_000277.1(PAH):c.838G>A(E280K) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

Comment:

This variant was found in at least one symptomatic individual and predicted to have a damaging effect on the protein. The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. It has also been reported to be associated with classic PKU and undetectable PAH enzyme activity (PMID: 12655546 (2003), 22763404(2012), 23500595 (2013), and 30963030 (2019)).

Comment:

The alteration results in an amino acid change:_x000D_ _x000D_ The c.838G>A (p.E280K) alteration is located in coding exon 7 of the PAH gene. This alteration results from a G to A substitution at nucleotide position 838, causing the glutamic acid (E) at amino acid position 280 to be replaced by a lysine (K). The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the PAH c.838G>A alteration was observed in 0.006% (16/282,678) of total alleles studied, with a frequency of 0.008% (10/128,998) in the European (non-Finnish) subpopulation. The alteration has been observed in affected individuals:_x000D_ _x000D_ This alteration has been reported homozygous or compound heterozygous with another mutation in PAH in multiple unrelated patients with phenylalanine hydroxylase (PAH) deficiency (Lyonnet, 1989; Okano, 1991; Su, 2019). The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.E280 amino acid is conserved in available vertebrate species. Functional analysis reveals a damaging effect of the amino acid alteration: _x000D_ _x000D_ Functional analysis demonstrated that the E280K alteration decreases PAH activity significantly compared to wild-type (Zurflüh, 2008; Shi, 2012). Three-dimensional structural analysis of the protein reveals that this alteration is an active site mutation (Pey, 2003). The alteration is predicted deleterious by in silico modeling:_x000D_ _x000D_ The p.E280K alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). It is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000580). The variant is in trans with the other variant. Different missense changes at the same codon (p.Glu280Gln, p.Glu280Gly) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102864 , VCV000102866). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

Published functional studies demonstrate that E280K is associated no detectable residual enzyme activity (Pey et al., 2003; Pey et al., 2007); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurfluh et al. 2008); This variant is associated with the following publications: (PMID: 2014036, 21953985, 30747360, 9399896, 1971144, 25087612, 22975760, 23500595, 17935162, 25750018, 2564729, 28676969, 29499199, 29317692, 12655546, 9101291, 30037505, 30963030, 31355225, 31589614, 33101986, 17924342, 32778825, 29288420, 33375644)

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 280 of the PAH protein (p.Glu280Lys). This variant is present in population databases (rs62508698, gnomAD 0.008%). This missense change has been observed in individual(s) with phenylketonuria (PMID: 2014036, 2564729, 12655546, 17935162, 23500595). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 580). 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%. Experimental studies have shown that this missense change affects PAH function (PMID: 2014036, 12655546, 17935162, 21953985). For these reasons, this variant has been classified as Pathogenic.

Comment:

The PAH c.838G>A variant is predicted to result in the amino acid substitution p.Glu280Lys. This is a commonly reported pathogenic variant that, in the homozygous state, has been associated with classic phenylketonuria (PKU) (e.g., Couce et al. 2013. PubMed ID: 23500595; Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The p.Glu280 amino acid has been reported to be located in the active site, and in functional assays the p.Glu280Lys substitution has essentially abolished PAH enzyme activity and resulted in a PAH protein that is non-responsive to BH4 (e.g., Pey et al. 2003. PubMed ID: 12655546; Zurflüh et al. 2008. PubMed ID: 17935162). Different substitutions of the same amino acid (p.Glu280Ala, p.Glu280Gly) have also been reported to be causative for phenylalanine hydroxylase deficiency (e.g., Aulehla-Scholz and Heilbronner. 2003. PubMed ID: 12655553; Song et al. 2005. PubMed ID: 16256386). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Multiple independent submitters to ClinVar have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/580). In summary, this variant is interpreted 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
The molecular epidemiology of hyperphenylalaninemia in Uygur population: incidence from newborn screening and mutational spectra.	Su Y	Annals of translational medicine	2019	PMID: 31355225
The evaluation of phenylalanine levels in Estonian phenylketonuria patients during eight years by electronic laboratory records.	Lilleväli H	Molecular genetics and metabolism reports	2019	PMID: 30963030
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
Molecular epidemiology and BH4-responsiveness in patients with phenylalanine hydroxylase deficiency from Galicia region of Spain.	Couce ML	Gene	2013	PMID: 23500595
Mutation spectrum of the PAH gene in the PKU patients from Khorasan Razavi province of Iran.	Hamzehloei T	Gene	2012	PMID: 22763404
Protein stability and in vivo concentration of missense mutations in phenylalanine hydroxylase.	Shi Z	Proteins	2012	PMID: 21953985
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.	Zurflüh MR	Human mutation	2008	PMID: 17935162
Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH.	Pey AL	Human mutation	2003	PMID: 12655546
Molecular basis of phenylketonuria in Cuba.	Desviat LR	Human mutation	2001	PMID: 11524738
Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population genetic variation: the Quebec experience.	Carter KC	European journal of human genetics : EJHG	1998	PMID: 9781015
Human phenylalanine hydroxylase mutations and hyperphenylalaninemia phenotypes: a metanalysis of genotype-phenotype correlations.	Kayaalp E	American journal of human genetics	1997	PMID: 9399896
Prediction of multiple hypermutable codons in the human PAH gene: codon 280 contains recurrent mutations in Quebec and other populations.	Byck S	Human mutation	1997	PMID: 9101291
Molecular basis of phenotypic heterogeneity in phenylketonuria.	Okano Y	The New England journal of medicine	1991	PMID: 2014036
Recurrent mutation in the human phenylalanine hydroxylase gene.	Okano Y	American journal of human genetics	1990	PMID: 1971144
Molecular genetics of phenylketonuria in Mediterranean countries: a mutation associated with partial phenylalanine hydroxylase deficiency.	Lyonnet S	American journal of human genetics	1989	PMID: 2564729
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH	-	-	-	-
http://www.pahdb.mcgill.ca/	-	-	-	-
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Text-mined citations for rs62508698 ...

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 Nov 03, 2024

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.838G>A (p.Glu280Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs62508698 ...