VCV000000582.144 - ClinVar

NM_000277.3(PAH):c.782G>A (p.Arg261Gln)

Germline

Top reviewed classifications are shown here.

Submission summary:

32 submissions

32 submitters

3 conditions

Reviewed by expert panel

Pathogenic

Aug 2018 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.782G>A (p.Arg261Gln)

Variation ID: 582 Accession: VCV000000582.144

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12q23.2 12: 102852875 (GRCh38) [ NCBI UCSC ] 12: 103246653 (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	Nov 24, 2024	Aug 13, 2018

HGVS

Nucleotide	Protein	Molecular consequence
NM_000277.3:c.782G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000268.1:p.Arg261Gln	missense
NM_000277.2:c.782G>A
NM_001354304.2:c.782G>A	NP_001341233.1:p.Arg261Gln	missense
NC_000012.12:g.102852875C>T
NC_000012.11:g.103246653C>T
NG_008690.2:g.110536G>A
	P00439:p.Arg261Gln

... more HGVS ... less HGVS

Protein change

R261Q

Other names

p.R261Q:CGA>CAA
NM_000277.1(PAH):c.782G>A

Canonical SPDI

NC_000012.12:102852874: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.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00020

The Genome Aggregation Database (gnomAD) 0.00022

The Genome Aggregation Database (gnomAD), exomes 0.00022

Exome Aggregation Consortium (ExAC) 0.00027

1000 Genomes Project 30x 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00041

Links

ClinGen: CA251528 UniProtKB: P00439#VAR_000965 OMIM: 612349.0006 dbSNP: rs5030849 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	1508	1631

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 (19)	reviewed by expert panel	Aug 13, 2018	RCV000000612.107
not provided	Pathogenic (12)	criteria provided, multiple submitters, no conflicts	Mar 1, 2024	RCV000078530.50
PAH-related disorder	Pathogenic (1)	no assertion criteria provided	Nov 9, 2023	RCV003904790.3

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 13, 2018)	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: SCV000852142.4 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022	Publications: PubMed (3) PubMed: 17935162‚ 2014036‚ 25596310 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9e4b6d0e-936a-4cbe-a237-e66213b685d4 Comment: PAH-specific ACMG/AMP criteria applied: PP3: tools predict damaging; PS3: 15.5-30% activity (PMID:2014036; PMID:25596310); PM3_VeryStrong: L48S, R408W, S349P, R243X (PMID:25596310; PMID:17935162); PP4_Moderate: (PMID:25596310). In summary this … (more) PAH-specific ACMG/AMP criteria applied: PP3: tools predict damaging; PS3: 15.5-30% activity (PMID:2014036; PMID:25596310); PM3_VeryStrong: L48S, R408W, S349P, R243X (PMID:25596310; PMID:17935162); PP4_Moderate: (PMID:25596310). 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: (PP3, PS3, PM3_VeryStrong, PP4_Moderate). (less)
Pathogenic (Dec 04, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281282.2 First in ClinVar: May 29, 2016 Last updated: Oct 09, 2016
Pathogenic (May 18, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611234.1 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Pathogenic (Jul 14, 2016)	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: SCV000696466.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (2) PubMed: 21871829‚ 26666653 Comment: Variant summary: The PAH c.782G>A (p.Arg261Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. … (more) Variant summary: The PAH c.782G>A (p.Arg261Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. Arg261 is highly conserved across species and is located in the Aromatic amino acid hydroxylase, C-terminal of the Phenylalanine-4-hydroxylase protein.This variant was found in 33/121376 control chromosomes at a frequency of 0.0002719, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in many PKU and HPA patients in homozygous or compound heterozygous state, and is considered a commonly known pathogenic PAH variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Jan 25, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000110386.8 First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH Number of individuals with the variant: 16 Sex: mixed
Pathogenic (May 28, 2019)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV001138801.1 First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020
Likely pathogenic (Nov 12, 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: SCV001194219.2 First in ClinVar: Apr 06, 2020 Last updated: Jul 06, 2020	Publications: PubMed (10) PubMed: 12409276‚ 23792259‚ 2574153‚ 8889590‚ 19394257‚ 22513348‚ 17935162‚ 12655546‚ 15557004‚ 10479481 Comment: NM_000277.1(PAH):c.782G>A(R261Q) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the R261Q variant can be associated with classic or … (more) NM_000277.1(PAH):c.782G>A(R261Q) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the R261Q variant can be associated with classic or variant PKU. Sources cited for classification include the following: PMID 12409276, 23792259, 2574153, 8889590, 19394257, 22513348, 17935162, 12655546, 15557004 and 10479481. Classification of NM_000277.1(PAH):c.782G>A(R261Q) is based on the following criteria: This variant 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 (Oct 04, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Knight Diagnostic Laboratories, Oregon Health and Sciences University Accession: SCV001448773.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Number of individuals with the variant: 1 Clinical Features: Global developmental delay (present) , Muscular hypotonia (present) , Strabismus (present) , Hypermetropia (present) , Dysphagia (present) , Short phalanx of finger (present) , Delayed … (more) Global developmental delay (present) , Muscular hypotonia (present) , Strabismus (present) , Hypermetropia (present) , Dysphagia (present) , Short phalanx of finger (present) , Delayed speech and language development (present) , Microcephaly (present) , Wide mouth (present) , Motor delay (present) , Myopathy (present) , Joint hypermobility (present) , Epicanthus (present) , Clinodactyly of the 5th finger (present) , Sensorineural hearing loss (present) , Short stature (present) , Decreased body weight (present) , Pes planus (present) , Widely spaced teeth (present) (less) Sex: female
Pathogenic (Sep 13, 2019)	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: SCV000888353.2 First in ClinVar: Dec 15, 2018 Last updated: Jan 26, 2021	Publications: PubMed (8) PubMed: 9634518‚ 16755493‚ 18447256‚ 23842451‚ 8487271‚ 25596310‚ 17935162‚ 10479481 Comment: Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this … (more) Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function. (less)
Pathogenic (Jul 10, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Phenylketonuria Affected status: no Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001761116.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Clinical Features: Autistic behavior (present) , Delayed speech and language development (present) , Pes planus (present) Secondary finding: no
Pathogenic (Jan 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: yes Allele origin: germline	3billion Accession: SCV002059132.1 First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022	Publications: PMID:2574153 PMID:2574153 PMID:17935162 PMID:17935162 PMID:25596310 PMID:25596310 PMID:7556322 PMID:7556322 PMID:2014036 PMID:2014036 Comment: Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000582, PMID:2574153, PS1_S). The … (more) Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000582, PMID:2574153, PS1_S). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 25596310, 17935162) (PM3_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25596310, 2014036, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.985, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000216, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102832, PMID:7556322,26666653, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Autistic behavior (present) , Global developmental delay (present)
Uncertain significance (Sep 19, 2023)	criteria provided, single submitter (Zastrow et al. (Hum Mutat. 2018)) Method: clinical testing	Phenylketonuria (Autosomal recessive inheritance) Affected status: yes Allele origin: inherited	Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences Accession: SCV004035233.1 First in ClinVar: Sep 23, 2023 Last updated: Sep 23, 2023	Publications: PubMed (1) PubMed: 26351554 Comment: uncertain (or unknown) significance Age: 0-9 years Sex: male Ethnicity/Population group: turkish Geographic origin: west azerbaijan (Iran)
Pathogenic (Jun 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002016475.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Phenylketonuria Affected status: yes Allele origin: germline	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251468.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (4) PubMed: 20301677‚ 2574153‚ 17935162‚ 16765994 Comment: The PAH c.782G>A (p.R261Q) missense variant has been reported in the compound heterozygous or homozygous state in individuals with phenylketonuria (PMID: 2574153; 17935162; 16765994) Number of individuals with the variant: 1
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755370.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022	Indication for testing: Phenylketonuria
Pathogenic (Oct 01, 2021)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000239072.16 First in ClinVar: Jul 18, 2015 Last updated: Mar 04, 2023	Comment: In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 23559577, … (more) In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 23559577, 19036622, 12655546, 10479481, 30747360, 26655635, 26759449, 26919687, 24401910, 25596310, 21953985, 2574153, 24296287, 26803807, 27682710, 11999982, 25750018, 27264808, 28676969, 22975760, 23500595, 9323556, 19194782, 29499199, 30037505, 27121329, 21527427, 8825928, 30963030, 31355225, 31028937, 30275481, 34426522, 31589614, 32905092, 33101986, 8188310, 32853555, 1915502, 1677425, 32778825, 33465300, 29288420, 8445616, 33375644, 17935162, 2014036, 8487271) (less)
Pathogenic (Jan 31, 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: SCV000629215.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 28492532‚ 2574153‚ 16765994‚ 10479481‚ 17935162‚ 25596310 Comment: This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 261 of the PAH protein (p.Arg261Gln). … (more) This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 261 of the PAH protein (p.Arg261Gln). This variant is present in population databases (rs5030849, gnomAD 0.04%). This missense change has been observed in individual(s) with PKU (PMID: 2574153, 16765994). ClinVar contains an entry for this variant (Variation ID: 582). 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: 10479481, 17935162, 25596310). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Phenylketonuria Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051901.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Pathogenic (Mar 28, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004201331.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005061253.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Comment: The observed missense c.782G>A (p.Arg261Gln) variant in PAH gene has been reported previously in multiple individuals affected with phenylketonuria (Wang et al. 2007; Jeannesson-Thivisol et … (more) The observed missense c.782G>A (p.Arg261Gln) variant in PAH gene has been reported previously in multiple individuals affected with phenylketonuria (Wang et al. 2007; Jeannesson-Thivisol et al. 2015). Experimental studies show this variant produced very low levels of PAH activity (Danecka et al. 2015; Jeannesson-Thivisol et al. 2015). The p.Arg261Gln variant is present with an allele frequency of 0.02% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg261Gln in PAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 261 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of metabolism/homeostasis (present)
Pathogenic (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249180.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: PAH: PM3:Very Strong, PS3, PM2, PP4:Moderate, PP3 Number of individuals with the variant: 7
Pathogenic (Oct 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Phenylketonuria (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute Additional submitter: Shariant Australia, Australian Genomics Accession: SCV005398976.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (1) PubMed: 26666653 Comment: Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more) Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (61 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated biopterin_H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar and has been observed as homozygous or compound heterozygous in individuals with classical PKU, and also in some individuals with mild PKU (PMID: 26666653). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
Pathogenic (Feb 13, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005414112.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Publications: PubMed (4) PubMed: 25596310‚ 34828281‚ 36046396‚ 36537053 Comment: PP3, PP4_moderate, PM3_very_strong, PS3 Number of individuals with the variant: 5
Pathogenic (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Phenylketonuria Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001453105.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 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: SCV001739558.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001975970.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Pathogenic (Nov 09, 2023)	no assertion criteria provided Method: clinical testing	PAH-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004724094.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: The PAH c.782G>A variant is predicted to result in the amino acid substitution p.Arg261Gln. This variant has been documented in numerous studies to be causative … (more) The PAH c.782G>A variant is predicted to result in the amino acid substitution p.Arg261Gln. This variant has been documented in numerous studies to be causative for phenylalanine hydroxylase deficiency (e.g., Bénit et al. 1999. PubMed ID: 10479481; Shi et al. 2012. PubMed ID: 21953985; Couce et al. 2013. PubMed ID: 23500595). In functional studies, the p.Arg261Gln substitution has been reported to reduce PAH enzyme activity to ~10-40% of control (e.g., Zurflüh et al. 2008. PubMed ID: 17935162; Danecka et al. 2015. PubMed ID: 25596310). The p.Arg261Gln substitution has been reported to result in a mutant PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel and multiple other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/582/). Based on these observations, we also classify the c.782G>A (p.Arg261Gln) variant as pathogenic. (less)
Pathogenic (Aug 15, 2007)	no assertion criteria provided Method: literature only	PHENYLKETONURIA Affected status: not provided Allele origin: germline	OMIM Accession: SCV000020762.68 First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 2574153‚ 1971144‚ 8487271‚ 17630668 Superti-Furga, A., Steinmann, B., (more...) Superti-Furga, A., Steinmann, B., Duc, G., Gitzelmann, R. Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase arg261-to-gln mutation. Europ. J. Pediat. 150: 493-497, 1991. Comment on evidence: Abadie et al. (1989) presented evidence that CpG dinucleotides represent mutation hotspots in phenylketonuria (PKU; 261600). Starting with the observation that the PAH gene contains … (more) Abadie et al. (1989) presented evidence that CpG dinucleotides represent mutation hotspots in phenylketonuria (PKU; 261600). Starting with the observation that the PAH gene contains 22 CpG dinucleotides including 5 doublets in exon 7, they carried out sequence analysis of exon 7 in 20 unrelated PAH-deficient kindreds of Mediterranean ancestry. This procedure resulted in the detection of 2 novel missense mutations whose location and nature (CG-to-CA and CG-to-TG) were consistent with the accidental deamination of a 5-methylcytosine in a CpG doublet: codon 261 (arg to gln, or R261Q) and codon 252 (arg to trp, or R252W; 612349.0007). In the Swiss population, Okano et al. (1990) found an arg158-to-gln mutation (R158Q; 612349.0010) as the basis of phenylketonuria. The substitution was in exon 5; an arg261-to-gln mutation in exon 7 was apparently an accompanying silent change. Expression analysis in heterozygous mammalian cells after site-directed mutagenesis demonstrated that indeed the arg158-to-gln mutation was the cause of PKU, and that the other mutation was silent. In Zurich, Superti-Furga et al. (1991) observed intrauterine growth retardation, microcephaly, and developmental delay in 2 first cousins whose mothers, 24- and 23-year-old sisters, had blood phenylalanine concentrations of approximately 1.2 mmol/l but had never been treated and had no overt mental retardation. Both mothers were shown to be homozygous for the arg261-to-gln mutation. This experience indicates that the homozygous state of this mutation is accompanied by only mild clinical manifestations but sufficient elevation of blood phenylalanine to cause maternal PKU syndrome in offspring. Kleiman et al. (1993) studied a family in which of 2 of 3 sibs had classic PKU and were compound heterozygotes for the R261Q mutation. Both PKU children, as well as their non-PKU brother, had microcephaly with head circumference below the second percentile; the IQ of the non-PKU boy was 89, while that of his parents was 100. The findings suggested maternal PKU, and further study demonstrated that the mother was homozygous for the R261Q mutation. She was found, however, to be well adjusted socially and worked as a school teacher. In patients with PKU from the Old Order Amish in Lancaster County, Pennsylvania, Wang et al. (2007) identified compound heterozygosity for 2 PAH mutations: R261Q and a 3-bp deletion at codon 94 (612349.0030). The incidence of PKU in the Lancaster County Amish was 1 in 10,000, similar to that in other populations. (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: SCV001931825.1 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	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: SCV001956078.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (-)	no classification provided Method: literature only	Phenylketonuria Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000324888.2 First in ClinVar: Oct 23, 2016 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1504 BookShelf: NBK1504
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: SCV000119697.1 First in ClinVar: Mar 19, 2014 Last updated: Mar 19, 2014
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Comment:

PAH-specific ACMG/AMP criteria applied: PP3: tools predict damaging; PS3: 15.5-30% activity (PMID:2014036; PMID:25596310); PM3_VeryStrong: L48S, R408W, S349P, R243X (PMID:25596310; PMID:17935162); PP4_Moderate: (PMID:25596310). 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: (PP3, PS3, PM3_VeryStrong, PP4_Moderate).

Comment:

Variant summary: The PAH c.782G>A (p.Arg261Gln) variant involves the alteration of a conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. Arg261 is highly conserved across species and is located in the Aromatic amino acid hydroxylase, C-terminal of the Phenylalanine-4-hydroxylase protein.This variant was found in 33/121376 control chromosomes at a frequency of 0.0002719, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in many PKU and HPA patients in homozygous or compound heterozygous state, and is considered a commonly known pathogenic PAH variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

NM_000277.1(PAH):c.782G>A(R261Q) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Please note that the R261Q variant can be associated with classic or variant PKU. Sources cited for classification include the following: PMID 12409276, 23792259, 2574153, 8889590, 19394257, 22513348, 17935162, 12655546, 15557004 and 10479481. Classification of NM_000277.1(PAH):c.782G>A(R261Q) is based on the following criteria: This variant 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:

Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Assessment of experimental evidence suggests this variant results in abnormal protein function.

Comment:

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000582, PMID:2574153, PS1_S). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 25596310, 17935162) (PM3_VS). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25596310, 2014036, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.985, 3CNET: 0.992, PP3_P). A missense variant is a common mechanism associated with Phenylketonuria (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000216, PM2_M). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102832, PMID:7556322,26666653, PM5_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25087612, 23559577, 19036622, 12655546, 10479481, 30747360, 26655635, 26759449, 26919687, 24401910, 25596310, 21953985, 2574153, 24296287, 26803807, 27682710, 11999982, 25750018, 27264808, 28676969, 22975760, 23500595, 9323556, 19194782, 29499199, 30037505, 27121329, 21527427, 8825928, 30963030, 31355225, 31028937, 30275481, 34426522, 31589614, 32905092, 33101986, 8188310, 32853555, 1915502, 1677425, 32778825, 33465300, 29288420, 8445616, 33375644, 17935162, 2014036, 8487271)

Comment:

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 261 of the PAH protein (p.Arg261Gln). This variant is present in population databases (rs5030849, gnomAD 0.04%). This missense change has been observed in individual(s) with PKU (PMID: 2574153, 16765994). ClinVar contains an entry for this variant (Variation ID: 582). 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: 10479481, 17935162, 25596310). For these reasons, this variant has been classified as Pathogenic.

Comment:

The observed missense c.782G>A (p.Arg261Gln) variant in PAH gene has been reported previously in multiple individuals affected with phenylketonuria (Wang et al. 2007; Jeannesson-Thivisol et al. 2015). Experimental studies show this variant produced very low levels of PAH activity (Danecka et al. 2015; Jeannesson-Thivisol et al. 2015). The p.Arg261Gln variant is present with an allele frequency of 0.02% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). The amino acid change p.Arg261Gln in PAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Arg at position 261 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.

Comment:

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (61 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated biopterin_H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar and has been observed as homozygous or compound heterozygous in individuals with classical PKU, and also in some individuals with mild PKU (PMID: 26666653). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Comment:

The PAH c.782G>A variant is predicted to result in the amino acid substitution p.Arg261Gln. This variant has been documented in numerous studies to be causative for phenylalanine hydroxylase deficiency (e.g., Bénit et al. 1999. PubMed ID: 10479481; Shi et al. 2012. PubMed ID: 21953985; Couce et al. 2013. PubMed ID: 23500595). In functional studies, the p.Arg261Gln substitution has been reported to reduce PAH enzyme activity to ~10-40% of control (e.g., Zurflüh et al. 2008. PubMed ID: 17935162; Danecka et al. 2015. PubMed ID: 25596310). The p.Arg261Gln substitution has been reported to result in a mutant PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). This variant is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel and multiple other outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/582/). Based on these observations, we also classify the c.782G>A (p.Arg261Gln) variant 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
Hyperphenylalaninemias genotyping: Results of over 60 years of history in Lombardy, Italy.	Rovelli V	Endocrinology, diabetes & metabolism	2023	PMID: 36537053
The analysis of using a panel of the most common variants in the PAH gene for the newborn screening in Ukraine.	Fishchuk L	Molecular genetics and metabolism reports	2022	PMID: 36046396
An Updated PAH Mutational Spectrum of Phenylketonuria in Mexican Patients Attending a Single Center: Biochemical, Clinical-Genotyping Correlations.	Vela-Amieva M	Genes	2021	PMID: 34828281
Phenylalanine Hydroxylase Deficiency.	Adam MP	-	2017	PMID: 20301677
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
Mutation analysis of the phenylalanine hydroxylase gene in Azerbaijani population, a report from West Azerbaijan province of Iran.	Bagheri M	Iranian journal of basic medical sciences	2015	PMID: 26351554
Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.	Danecka MK	Journal of medical genetics	2015	PMID: 25596310
Tetrahydrobiopterin responsiveness in phenylketonuria: prediction with the 48-hour loading test and genotype.	Anjema K	Orphanet journal of rare diseases	2013	PMID: 23842451
Mutation analysis in hyperphenylalaninemia patients from South Italy.	Trunzo R	Clinical biochemistry	2013	PMID: 23792259
Five novel mutations and two large deletions in a population analysis of the phenylalanine hydroxylase gene.	Groselj U	Molecular genetics and metabolism	2012	PMID: 22513348
Phenylalanine hydroxylase deficiency: molecular epidemiology and predictable BH4-responsiveness in South Portugal PKU patients.	Rivera I	Molecular genetics and metabolism	2011	PMID: 21871829
Genotype-predicted tetrahydrobiopterin (BH4)-responsiveness and molecular genetics in Croatian patients with phenylalanine hydroxylase (PAH) deficiency.	Karacić I	Molecular genetics and metabolism	2009	PMID: 19394257
Screening for six Mediterranean mutations in 90 Egyptian patients with phenylketonuria.	Effat LK	Bratislavske lekarske listy	2008	PMID: 18447256
Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency.	Zurflüh MR	Human mutation	2008	PMID: 17935162
Phenylalanine hydroxylase deficiency exhibits mutation heterogeneity in two large old order Amish settlements.	Wang H	American journal of medical genetics. Part A	2007	PMID: 17630668
The importance of arginine mutation for the evolutionary structure and function of phenylalanine hydroxylase gene.	Lüleyap HU	Mutation research	2006	PMID: 16765994
Frequencies of phenylalanine hydroxylase mutations I65T, R252W, R261Q, R261X, IVS10nt11, V388M, R408W, Y414C, and IVS12nt1 in Minas Gerais, Brazil.	Santos LL	Genetics and molecular research : GMR	2006	PMID: 16755493
Correction of kinetic and stability defects by tetrahydrobiopterin in phenylketonuria patients with certain phenylalanine hydroxylase mutations.	Erlandsen H	Proceedings of the National Academy of Sciences of the United States of America	2004	PMID: 15557004
Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH.	Pey AL	Human mutation	2003	PMID: 12655546
Two novel genetic lesions and a common BH4-responsive mutation of the PAH gene in Italian patients with hyperphenylalaninemia.	Bardelli T	Molecular genetics and metabolism	2002	PMID: 12409276
The mutant genotype is the main determinant of the metabolic phenotype in phenylalanine hydroxylase deficiency.	Bénit P	Molecular genetics and metabolism	1999	PMID: 10479481
A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype.	Guldberg P	American journal of human genetics	1998	PMID: 9634518
Phenylalanine hydroxylase deficiency in a population in Germany: mutational profile and nine novel mutations.	Guldberg P	Human mutation	1996	PMID: 8889590
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
Phenylketonuria: variable phenotypic outcomes of the R261Q mutation and maternal PKU in the offspring of a healthy homozygote.	Kleiman S	Journal of medical genetics	1993	PMID: 8487271
Molecular basis of phenotypic heterogeneity in phenylketonuria.	Okano Y	The New England journal of medicine	1991	PMID: 2014036
Maternal phenylketonuria syndrome in cousins caused by mild, unrecognized phenylketonuria in their mothers homozygous for the phenylalanine hydroxylase Arg-261-Gln mutation.	Superti-Furga A	European journal of pediatrics	1991	PMID: 1915502
Recurrent mutation in the human phenylalanine hydroxylase gene.	Okano Y	American journal of human genetics	1990	PMID: 1971144
CpG dinucleotides are mutation hot spots in phenylketonuria.	Abadie V	Genomics	1989	PMID: 2574153
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=PAH	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/9e4b6d0e-936a-4cbe-a237-e66213b685d4	-	-	-	-
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Text-mined citations for rs5030849 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000277.3(PAH):c.782G>A (p.Arg261Gln)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs5030849 ...