12-102866632-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PP4_ModeratePP3PM3PS3

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251530/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21O:2

Conservation

PhyloP100: 5.24

Variant links:

Genes affected

PAH (HGNC:8582): (phenylalanine hydroxylase) This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria. [provided by RefSeq, Aug 2017]

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 9 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAH	NM_000277.3 link	c.473G>A	p.Arg158Gln	missense_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.473G>A	p.Arg158Gln	missense_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.473G>A	p.Arg158Gln	missense_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.807+1405C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PAH	ENST00000553106.6 link	c.473G>A	p.Arg158Gln	missense_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1	P00439
PAH	ENST00000549111.5 link	n.569G>A		non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7 link	c.458G>A	p.Arg153Gln	missense_variant	Exon 6 of 14	5		ENSP00000303500.2	J3KND8
PAH	ENST00000551988.5 link	n.530+10830G>A		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000915

AC:

AN:

251364

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000147

AC:

215

AN:

1461514

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000184

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000658

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000230

Hom.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000988

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:12Other:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 1989

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

PS3+PM3_VS+PP3+PP4_M -

Jan 05, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Jul 28, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 03, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2024

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a single nucleotide substitution (G>A) at position 473 of the coding sequence of the PAH gene that results in an arginine to glutamine amino acid change at residue 158 of the phenylalanine hydroxylase protein. This residue falls in the catalytic domain of the protein which is important for the binding of iron, cofactor, and substrate (PMID: 23457044). This is a previously reported variant (ClinVar 587) that has been classified as pathogenic by an expert panel (ClinGen SCV000852101.4). This variant has been observed in individuals affected by phenylketonuria and hyperphenylalaninemia (PMID: 2014036, 23500595, 10479481, 24368688). This variant is present in 225 of 1613598 alleles (0.014%) in the gnomAD v4.0.0 population dataset. Multiple bioinformatic tools predict that this amino acid change would be damaging, and the Arg158 residue at this position is highly conserved across the vertebrate species examined. Studies examining the functional consequence of this variant demonstrate significantly impaired enzymatic activity (PMID: 2014036, 19036622, 23500595). Based upon the evidence, we consider this variant to be pathogenic. ACMG Criteria: PM3, PP3, PP4, PS3 -

not provided

Pathogenic:8Other:1

Oct 26, 2016

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 04, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Associated with significantly reduced enzyme activity compared to wild type (Steventon et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; BH4 responsiveness has been inconsistent in patients with R158Q (Zurfluh et al., 2008); This variant is associated with the following publications: (PMID: 26210745, 27264808, 25087612, 30963030, 31355225, 17924342, 22975760, 12655546, 2014036, 21953985, 19036622, 2606484, 17935162, 28754886, 29288420, 29111448, 28956315, 29316886, 28676969, 23500595, 25750018, 26803807, 29499199, 30747360, 31589614, 33101986, 8188310) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported in individuals affected by Phenylketonuria (PKU) (PMIDs: 2606484 (1989), 12655546 (2003), 30747360 (2019), and 31355225 (2019)). Functional studies show that this variant is predicted to negatively impact protein function (PMIDs: 12655546 (2003), 17935162 (2008), 19036622 (2009), 21953985 (2012), and 25750018 (2015)). Based on the available information, this variant is classified as pathogenic. -

Jul 02, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PM2_moderate, PM3_very_strong, PM5, PS3 -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PAH-related disorder

Pathogenic:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH c.473G>A variant is predicted to result in the amino acid substitution p.Arg158Gln. This variant has been commonly observed in individuals with phenylalanine hydroxylase deficiency and is associated clinically with phenylketonuria (PKU) (e.g., Dworniczak et al. 1989. PubMedID: 2606484; Bénit et al. 1999. PubMed ID: 10479481; Couce et al. 2013. PubMed ID: 23500595; Ho et al. 2014. PubMed ID: 24368688; Danecka et al. 2015. PubMed ID: 25596310). In functional studies, p.Arg158Gln substitution has been reported to reduce enzyme activity to 10% or less relative to control (Zurflüh et al. 2008. PubMed ID: 17935162; Steventon et al. 2009. PubMed ID: 19036622). This substitution has been reported to lead to a PAH protein that is responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162; Couce et al. 2013. PubMed ID: 23500595). This variant is reported in 0.019% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as by many other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/587/). Based on these observations, we also interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.81

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

4.5

H;.

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.9

D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.95

MVP

0.99

MPC

0.25

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.86

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over