rs5030841

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP4_ModeratePP1PP3PM3PS3

This summary comes from the ClinGen Evidence Repository: The c.143T>C (p.Leu48Ser) variant in PAH has been reported multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID:26322415, 16879198, 1679030). This variant has a frequency that is higher than the suggested cutoff for PM2 by the PAH VCEP (MAF=0.00026). This variant has 39% residual activity (PS3, PMID:17935162). This variant was detected in trans with p.G247R (LP, 2 submitters) PM3, PMID:26322415). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Cosegregation with PKU in 2 siblings for 2 unrelated families was reported ( PMID:23430547). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3, PP1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA251539/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000077 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:21O:1

Conservation

PhyloP100: 5.97

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 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.

PP1

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.143T>C	p.Leu48Ser	missense_variant	Exon 2 of 13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 link	c.143T>C	p.Leu48Ser	missense_variant	Exon 3 of 14		NP_001341233.1
PAH	XM_017019370.2 link	c.143T>C	p.Leu48Ser	missense_variant	Exon 2 of 7		XP_016874859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 link	c.143T>C	p.Leu48Ser	missense_variant	Exon 2 of 13	1	NM_000277.3	ENSP00000448059.1		P00439

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

251416

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135872

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000767

AC:

112

AN:

1461054

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

726872

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000855

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000197

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000982

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000155

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:13

Aug 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 48 of the PAH protein (p.Leu48Ser). This variant is present in population databases (rs5030841, gnomAD 0.03%). This missense change has been observed in individuals with classical and variant phenylketonuria (PKU) (PMID: 1679030, 9399896, 23430547, 23500595). ClinVar contains an entry for this variant (Variation ID: 608). 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: 11461190, 23500595, 25596310). For these reasons, this variant has been classified as Pathogenic. -

Mar 28, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP2,PP3. -

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2019

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.143T>C (p.Leu48Ser) variant in PAH has been reported multiple individuals with mild and classic PKU (BH4 deficiency excluded). (PP4_Moderate; PMID: 26322415, 16879198, 1679030). This variant has a frequency that is higher than the suggested cutoff for PM2 by the PAH VCEP (MAF=0.00026). This variant has 39% residual activity (PS3, PMID: 17935162). This variant was detected in trans with p.G247R (LP, 2 submitters) PM3, PMID: 26322415). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Cosegregation with PKU in 2 siblings for 2 unrelated families was reported ( PMID: 23430547). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3, PP1, PP3. -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 23, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.012%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17935162). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.97; 3Cnet: 0.98). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 26481238). A different missense change at the same codon (p.Leu48Val) has been reported to be associated with PAH related disorder (PMID: 31623983). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 08, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000277.1(PAH):c.143T>C(L48S) 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 16879198, 22513348, 12501224, 9521426, 8889590, 23500595, 23430547, 21953985, 17935162 and 1679030. Classification of NM_000277.1(PAH):c.143T>C(L48S) 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.â€šÃ„Ã¶âˆšÃ‘âˆšÂ£ -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 15, 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.143T>C (p.Leu48Ser) variant located in the ACT domain (via InterPro) causes a missense change involving a conserved nucleotide, to which 5/5 in silico tools predict a damaging outcome. The variant of interest was found in the large, broad control population, ExAC, with an allele frequency of 10/121396 (1/12135), which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. The variant of interest has been reported in multiple affected individuals as homozygous and compound heterozygous and had been implicated to cause a mild PKU phenotype. In addition, multiple clinical diagnostic laboratories/databases cite the variant as "pathogenic." Therefore, the variant of interest has been classified as "pathogenic." -

May 02, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:6Other:1

Oct 12, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with a variable phenotype that ranges from hyperphenylalaninemia to classic PKU (PMIDs: 25596310 (2015), 23430547 (2013), 21953985 (2012), 16879198 (2006), and 1679030 (1991)). The variant occurs in multiple cases with a lone recessive pathogenic/likely pathogenic variant in the same gene, and several have a phenotype known to be consistent with disease. In addition, experimental studies have shown that this variant has deleterious effects on PAH enzyme activity and protein expression (PMIDs: 25596310 (2015), 23500595 (2013), 21953985 (2012), and 17935162 (2008)). -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PAH: PM3:Very Strong, PM2, PP4:Moderate, PS3:Supporting -

Aug 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional studies demonstrate p.(L48S) is associated with significantly reduced enzyme activity compared to wildtype (PMID: 25596310, 26803807); 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: 21953985, 25525159, 1679030, 30963030, 34900593, 23500595, 25087612, 11461190, 17935162, 23559577, 22975760, 23430547, 26803807, 9323556, 28676969, 9399896, 31355225, 26322415, 16879198, 34426522, 31589614, 33101986, 8592329, 32778825, 33465300, 36537053, 36646061, 36672771, 35405047, 25596310, 37189584) -

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 13, 2012

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 29, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 13, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PP4_moderate, PM3, PS3 -

PAH-related disorder

Pathogenic:1

Feb 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PAH c.143T>C variant is predicted to result in the amino acid substitution p.Leu48Ser. This variant has been well documented as causative for phenylalanine hydroxylase deficiency (e.g., Couce et al. 2013. PubMed ID: 23500595; Heintz et al. 2013. PubMed ID: 23559577, Table S3 in Hillert et al. 2020. PubMed ID: 32668217). The c.143T>C variant has been reported to reduce the activity of the PAH protein to 39% of wild-type, and individuals with the p.Leu48Ser substitution are often found to be responsive to tetrahydrobiopterin (BH4). However, it should be noted that there is some inconsistency in BH4-responsivness by individuals carrying this particular variant (Zurflüh et al. 2008. PubMed ID: 17935162). The ClinGen PAH Variant Curation Expert Panel, as well as several other labs, classify this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/608/). Based on these observations, we also interpret this variant as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Apr 20, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.143T>C (p.L48S) alteration is located in exon 2 (coding exon 2) of the PAH gene. This alteration results from a T to C substitution at nucleotide position 143, causing the leucine (L) at amino acid position 48 to be replaced by a serine (S). Based on data from the Genome Aggregation Database (gnomAD), the PAH c.143T>C alteration was observed in 0.012% (34/282,822) of total alleles studied, with a frequency of 0.025% (9/35,440) in the Latino subpopulation. This is a recurrent mutation, reported in multiple unrelated patients with mild and classic PKU (Konecki, 1991; Couce, 2013; Djordjevic, 2013; Gundorova, 2019; Su, 2019). This amino acid position is highly conserved in available vertebrate species. Functional analysis of the p.L48S alteration, either homozygous or compound heterozygous with another PAH mutation, found that it is associated with reduced enzyme activity compared to wildtype (Waters, 2001; Danecka, 2015; Shen, 2016). The p.L48S alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D;D;D

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.95

D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.4

H;.;.;.

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.5

D;D;D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.99

MVP

1.0

MPC

0.27

ClinPred

0.99

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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