NM_000277.3(PAH):c.473G>A (p.Arg158Gln) AND Phenylketonuria

Germline classification:: Pathogenic (12 submissions)
Last evaluated:: Aug 5, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000000618.94

Allele description [Variation Report for NM_000277.3(PAH):c.473G>A (p.Arg158Gln)]

NM_000277.3(PAH):c.473G>A (p.Arg158Gln)

Gene:

PAH:phenylalanine hydroxylase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q23.2

Genomic location:

Preferred name:

NM_000277.3(PAH):c.473G>A (p.Arg158Gln)

Other names:

p.R158Q:CGG>CAG; NM_000277.2(PAH):c.473G>A

HGVS:

NC_000012.12:g.102866632C>T
NG_008690.2:g.96779G>A
NM_000277.3:c.473G>AMANE SELECT
NM_001354304.2:c.473G>A
NP_000268.1:p.Arg158Gln
NP_000268.1:p.Arg158Gln
NP_001341233.1:p.Arg158Gln
NC_000012.11:g.103260410C>T
NM_000277.1:c.473G>A
NM_000277.2:c.473G>A
P00439:p.Arg158Gln
c.473G>A (p.Arg158Gln)

Protein change:

R158Q; ARG158GLN

Links:

UniProtKB: P00439#VAR_000901; OMIM: 612349.0010; dbSNP: rs5030843

NCBI 1000 Genomes Browser:

rs5030843

Molecular consequence:

NM_000277.3:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354304.2:c.473G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Phenylketonuria (PKU)
Synonyms:: Phenylketonurias; Oligophrenia phenylpyruvica; Folling disease
Identifiers:: MONDO: MONDO:0009861; MedGen: C0031485; Orphanet: 716; OMIM: 261600

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000020768	OMIM	no assertion criteria provided	Affects (Dec 1, 1989)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000324887	GeneReviews	no classification provided	not provided	germline	literature only
SCV000611233	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000629193	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 2014036, 10479481, 23500595, 24368688, 25596310, 14654665, 19036622, 28492532
SCV000696450	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 28, 2016)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17935162, 9634518, 26666653 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000746356	Genomic Research Center, Shahid Beheshti University of Medical Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 3, 2017)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000852101	ClinGen PAH Variant Curation Expert Panel	reviewed by expert panel (ClinGen PAH ACMG Specifications v1)	Pathogenic (Aug 5, 2018)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 19036622, 24368688, 23500595, 10479481, 2014036 Citation Link,
SCV001163725	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193837	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Pathogenic (Dec 9, 2019)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22513348, 2014036, 2606484, 12655546, 19036622, 21953985, 17935162 Citation Link,
SCV001455102	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002058800	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:2606484,
SCV004800897	Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only, clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	inherited	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
Tujia	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria.

Danecka MK, Woidy M, Zschocke J, Feillet F, Muntau AC, Gersting SW.

J Med Genet. 2015 Mar;52(3):175-85. doi: 10.1136/jmedgenet-2014-102621. Epub 2015 Jan 16.

PubMed [citation]

PMID:: 25596310

Structural studies on phenylalanine hydroxylase and implications toward understanding and treating phenylketonuria.

Erlandsen H, Patch MG, Gamez A, Straub M, Stevens RC.

Pediatrics. 2003 Dec;112(6 Pt 2):1557-65. Review.

PubMed [citation]

PMID:: 14654665

See all PubMed Citations (16)

PMC

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Details of each submission

From OMIM, SCV000020768.64

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 7 out of 94 phenylketonuria (PKU; 261600) alleles, Dworniczak et al. (1989) identified a G-to-A transition in nucleotide 695 in exon 5 of PAH. Twenty-four percent of the PKU alleles were in a background of haplotype 4; all 7 of the G-to-A transitions were on the haplotype 4 background. The base substitution predicted an arg158-to-gln (R158Q) change.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneReviews, SCV000324887.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV000611233.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000629193.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 158 of the PAH protein (p.Arg158Gln). This variant is present in population databases (rs5030843, gnomAD 0.02%). This missense change has been observed in individuals with PKU (PMID: 2014036, 10479481, 23500595, 24368688, 25596310). ClinVar contains an entry for this variant (Variation ID: 587). 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: 14654665, 19036622). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696450.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: The PAH c.473G>A (p.Arg158Gln) variant involves the alteration of a conserved nucleotide. The affected amino acid, Arg158, is located in the Aromatic amino acid hydroxylase, C-terminal domain. 4/5 in silico tools predict a damaging outcome for this variant, and the residual activity from in vitro cell based assays was reported to be 10% of wild type activity (Zurfluh_HM_2008 and BIOPKU database). This variant was found in 12/121256 control chromosomes at a frequency of 0.000099, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in numerous patients with classic or moderate PKU. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genomic Research Center, Shahid Beheshti University of Medical Sciences, SCV000746356.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen PAH Variant Curation Expert Panel, SCV000852101.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

PAH-specific ACMG/AMP criteria applied: PS3: R158Q is associated with very low levels (0.2-1.8%) of pah enzyme activity compared to wild-type. (PMID:2014036; PMID:19036622); PP3: tools predict damaging ; PP4_Moderate: BH4 testing showed responsive in a pt, pretreatment 1065uM (PMID:23500595); PM3_VeryStrong: in trans with 4 pathogenic variants: I48S, c.1315+1G>A, P281L, R261Ter. (PMID:23500595; PMID:10479481; PMID:24368688). 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: (PS3, PP3, PP4_Moderate, PM3_VeryStrong).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV001163725.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV001193837.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

NM_000277.1(PAH):c.473G>A(R158Q) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and is associated with classic or variant PKU. Sources cited for classification include the following: PMID 22513348, 2014036, 2606484, 12655546, 19036622, 21953985 and 17935162. Classification of NM_000277.1(PAH):c.473G>A(R158Q) 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV001455102.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From 3billion, SCV002058800.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000587, PMID:2606484, PS1_S). A different missense change at the same codon has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102693, PMID:1307609,NULL,32668217, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.965, 3CNET: 0.983, PP3_P). A missense variant is a common mechanism associated with Hyperphenylalaninemia (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000092, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital, SCV004800897.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Tujia	1	not provided	not provided	clinical testing	not provided

Description

PS3+PM3_VS+PP3+PP4_M

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 15, 2024

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