rs75166491

Positions:

chr12-102866633-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PS3PM3_StrongPP3PP4_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

14

4

1

Clinical Significance

Pathogenic reviewed by expert panel P:9O:1

Conservation

PhyloP100: 1.43

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 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/exons	MANE	Protein	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.472C>T	p.Arg158Trp	missense_variant	5/13	ENST00000553106.6	NP_000268.1
LOC124902999	XR_007063428.1 linkuse as main transcript	n.807+1406G>A		intron_variant, non_coding_transcript_variant
PAH	NM_001354304.2 linkuse as main transcript	c.472C>T	p.Arg158Trp	missense_variant	6/14		NP_001341233.1
PAH	XM_017019370.2 linkuse as main transcript	c.472C>T	p.Arg158Trp	missense_variant	5/7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.472C>T	p.Arg158Trp	missense_variant	5/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000549111.5 linkuse as main transcript	n.568C>T		non_coding_transcript_exon_variant	5/6	1
PAH	ENST00000307000.7 linkuse as main transcript	c.457C>T	p.Arg153Trp	missense_variant	6/14	5		ENSP00000303500
PAH	ENST00000551988.5 linkuse as main transcript	n.530+10829C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

5

AN:

152136

Hom.:

0

Cov.:

32

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

GnomAD3 exomes

AF:

0.0000278

AC:

7

AN:

251352

Hom.:

0

AF XY:

0.0000221

AC XY:

3

AN XY:

135836

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

27

AN:

1461492

Hom.:

0

Cov.:

30

AF XY:

0.0000179

AC XY:

13

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000171

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

5

AN:

152136

Hom.:

0

Cov.:

32

AF XY:

0.0000404

AC XY:

3

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000966

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000323

Hom.:

0

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.0000247

AC:

3

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 09, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 08, 2022	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 10, 2018	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). -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	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). 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%. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 12, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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:1Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2021	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) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.37

D

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

1.0

D;D

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.81

D

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.71

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.0

D

MutationAssessor

Pathogenic

4.5

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.81

D

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

D

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

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

LitVar

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

Other links and lift over

dbSNP: rs75166491; hg19: chr12-103260411; COSMIC: COSV61014403;