rs75166491

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PP3PS3PM3_StrongPP4_ModeratePM2

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). 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: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229570/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:10O:1

Conservation

PhyloP100: 1.43

Publications

22 publications found

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 Gene-Disease associations (from GenCC):

phenylketonuria
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
classic phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
maternal phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild hyperphenylalaninemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
mild phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PAH links:

LOC124902999 (HGNC:):

LOC124902999 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 13 ACMG points.

PS3

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

PM2

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
PAH	NM_000277.3 link	c.472C>T	p.Arg158Trp	missense_variant	Exon 5 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 link	c.472C>T	p.Arg158Trp	missense_variant	Exon 6 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.472C>T	p.Arg158Trp	missense_variant	Exon 5 of 7		XP_016874859.1
LOC124902999	XR_007063428.1 link	n.807+1406G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PAH	ENST00000553106.6 link	c.472C>T	p.Arg158Trp	missense_variant	Exon 5 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000549111.5 link	n.568C>T		non_coding_transcript_exon_variant	Exon 5 of 6	1
PAH	ENST00000307000.7 link	c.457C>T	p.Arg153Trp	missense_variant	Exon 6 of 14	5		ENSP00000303500.2
PAH	ENST00000551988.5 link	n.530+10829C>T		intron_variant	Intron 4 of 4	3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251352

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1461492

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727066

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33454

American (AMR)

AF:

0.0000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000171

AC:

AN:

1111704

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:8

Sep 16, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 08, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PAH c.472C>T (p.Arg158Trp) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251352 control chromosomes (gnomAD). c.472C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Shintaku_2003, Santos__2010, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in <10% of normal activity (Danecka_2015). In addition, another variant (p.Arg158Gln) at the same residue was found in many individuals affected Phenylketonuria and has been classified as pathogenic at our laboratory, indicating the arginine residue is critical for protein function. Five ClinVar submitters (evaluation after 2014, including one expert panel, ClinGen PAH Variant Curation Expert Panel) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 27, 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 tryptophan, which is neutral and slightly polar, at codon 158 of the PAH protein (p.Arg158Trp). This variant is present in population databases (rs75166491, gnomAD 0.01%). This missense change has been observed in individual(s) with phenylketonuria (PKU) (PMID: 10356314, 14681498, 19609714, 20082265, 23430918, 24130151, 24941924, 25894915, 26666653). ClinVar contains an entry for this variant (Variation ID: 102693). 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%. This variant disrupts the p.Arg158 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 2014036, 10479481, 23500595, 24368688, 25596310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Jan 21, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Mar 09, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 10, 2018

ClinGen PAH Variant Curation Expert Panel

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00019.; PP3: Predicted deleterious in SIFT, Polyphen-2, MutationTaster. REVEL=0.939; PS3: 2% mutant enzyme activity in BioPKU; PP4_Moderate: Detected in at least 3 patients with PAH deficiency. BH4 deficiency ruled out in 1 patient. (PMID:1307609; PMID:10429004; PMID:9634518); PM3_Strong: Detected with 3 pathogenic/likely pathogenic variants (PMID:14681498; PMID:23430918). 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: (PM2, PP3, PS3, PP4_Moderate, PM3_Strong). -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The missense variant c.472C>T (p.Arg158Trp) in PAH gene has been reported as homozygous or in combination with another PAH variant in multiple individuals affected with phenylketonuria (Santos LL et.al.,2010). Functional analysis found that R158W is associated with 1.8% residual enzyme activity compared to wild type (Danecka et al.,2015). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg158Trp variant is reported with allele frequency 0.003% in gnomAD exomes and novel in 1000 Genomes. The amino acid Arg at position 158 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg158Trp in PAH is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . -

not provided

Pathogenic:2Other:1

Sep 27, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The PAH c.472C>T (p.Arg158Trp) variant has been reported in the published literature in individuals with phenylketonuria, whom were either compound heterozygous or homozygous for the variant (PMIDs: 23430918 (2012), 20082265 (2010), 10394930 (1999), 9634518 (1998)). Functional evidence suggests that this variant may impact protein function ( Phenylalanine Hydroxylase Gene Locus-Specific Database (http://www.biopku.org/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Nov 22, 2021

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported homozygous in an individual with mild-moderate PKU (Jeannesson-Thivisol et al., 2015); however, this variant has also been identified in individuals with classic PKU (Yamashita et al., 1992; Bashyam et al., 2014; Jeannesson-Thivisol et al., 2015; Danecka et al., 2015); Published functional studies demonstrate p.(R158W) results in significantly reduced residual activity compared to wildtype (Danecka et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25750018, 34828281, 29413232, 25087612, 25596310, 1307609, 26666653, 24130151, 29499199, 30747360, 30275481, 32668217, 32778825, 33375644, 17935162, 17924342) -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

H;.

PhyloP100

1.4

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.99

MVP

0.99

MPC

0.24

ClinPred

1.0

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.98

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over