rs5030860

Positions:

chr12-102840474-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3PS3PM5PP4_ModeratePP3

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM5: c.1240T>C likely pathogenic in ClinVar; PP3: All computational evidence supports deleterious effect. REVEL=0.982; PS3: 50% activity, 50% immunoreactivity (PMID:2044609); PM3_VeryStrong: Patient #41 p.R408W / p.Y414C, Phe 744 @dx and two homozygous individuals. Total of 9 patients with this variant (PMID:22526846; PMID:17935162; PMID:9399896; PMID:21871829; PMID:26542770); PP4_Moderate: BH4 defect excluded in all patients (PMID:22526846). 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: (PM5, PP3, PS3, PM3_VeryStrong, PP4_Moderate). LINK:https://erepo.genome.network/evrepo/ui/classification/CA114362/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 1 hom. )

Consequence

PAH
ENST00000553106.6 missense

Scores

14

4

1

Clinical Significance

Pathogenic reviewed by expert panel P:28O:1

Conservation

PhyloP100: 7.63

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 11 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.

PM5

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.1241A>G	p.Tyr414Cys	missense_variant	12/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.1241A>G	p.Tyr414Cys	missense_variant	13/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.1241A>G	p.Tyr414Cys	missense_variant	12/13	1	NM_000277.3	ENSP00000448059	P1

Frequencies

GnomAD3 genomes

AF:

0.000256

AC:

39

AN:

152202

Hom.:

0

Cov.:

32

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000558

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000366

AC:

92

AN:

251440

Hom.:

0

AF XY:

0.000368

AC XY:

50

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000721

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.000365

AC:

533

AN:

1461726

Hom.:

1

Cov.:

31

AF XY:

0.000375

AC XY:

273

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

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:

0.000168

Gnomad4 NFE exome

AF:

0.000443

Gnomad4 OTH exome

AF:

0.000331

GnomAD4 genome

AF:

0.000256

AC:

39

AN:

152320

Hom.:

0

Cov.:

32

AF XY:

0.000175

AC XY:

13

AN XY:

74468

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:

0.0000941

Gnomad4 NFE

AF:

0.000558

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000434

Hom.:

1

Bravo

AF:

0.000246

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000465

AC:

4

ExAC

AF:

0.000494

AC:

60

Asia WGS

AF:

0.000289

AC:

2

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:18

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 18, 2016	Variant summary: The c.1241A>G variant affects a conserved nucleotide, resulting in amino acid change from Tyr to Cys. 5/5 in-silico tools predict damaging outcome for this variant. This variant is found in 60/121344 control chromosomes at a frequency of 0.0004945, which does not exceed maximal expected frequency of a pathogenic allele (0.0079057). This variant has been reported in numerous patients with PKU or HPA at homozygous or compound heterozygous state. In addition, multiple clinical laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant was classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Jul 27, 2018	PAH-specific ACMG/AMP criteria applied: PM5: c.1240T>C likely pathogenic in ClinVar; PP3: All computational evidence supports deleterious effect. REVEL=0.982; PS3: 50% activity, 50% immunoreactivity (PMID:2044609); PM3_VeryStrong: Patient #41 p.R408W / p.Y414C, Phe 744 @dx and two homozygous individuals. Total of 9 patients with this variant (PMID:22526846; PMID:17935162; PMID:9399896; PMID:21871829; PMID:26542770); PP4_Moderate: BH4 defect excluded in all patients (PMID:22526846). 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: (PM5, PP3, PS3, PM3_VeryStrong, PP4_Moderate). -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 12, 2019	NM_000277.1(PAH):c.1241A>G(Y414C) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency, and can be associated with any form of the disease. Sources cited for classification include the following: PMID 12655553, 22112818, 11385716, 22526846, 2014036, 23500595, 8889590, 12501224, 17935162, 18538294, 21953985 and 15557004. Classification of NM_000277.1(PAH):c.1241A>G(Y414C) 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	PAH:NM_000277.1:exon12:c.1241A>G:p.Tyr414Cys Sequence analysis reveals a heterozygous c.1241A>G (p.Tyr414Cys) variant in the PAH gene. This variant is observed in 99/277184 allelles in the gnomAD database. In silico predictions by multiple algorithms indicate that this variant is deleterious on the function of the protein. Multiple entries in the Clinvar database classified this variant as pathogenic. Therefore this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (PKU; MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from tyrosine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (100 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or very highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Biopterin_H domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is a well-reported variant and is commonly described as a mild PKU variant (ClinVar, PKU database, PMID: 30668579). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Site-directed mutagenesis studies have shown a reduction to 28-80% in PAH activity compared to wild-type (PMID: 30037505). In the BioPKU database, this variant is reported to result in 57% residual enzyme activity (BioPKU). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.035%). 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: 2014036, 2044609). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000000593). 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: 17935162, 21871829, 22526846, 26542770, 9399896). A different missense change at the same codon (p.Tyr414His) has been reported to be associated with PAH-related disorder (PMID: 32668217). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 08, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 414 of the PAH protein (p.Tyr414Cys). This variant is present in population databases (rs5030860, gnomAD 0.07%). This missense change has been observed in individual(s) with mild phenylketonuria (PKU) and non-PKU hyperphenylalaninemia (HPA) (PMID: 8556304, 9399896, 12655544, 20063067, 23764561). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 593). 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: 10479481, 17935162, 18538294, 19036622). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jan 02, 2024	PM5, PP3, PP4_Moderate, PS3_Very Strong -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Oct 31, 2018	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM1,PM3,PP3,PP2. -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 2016	The p.Tyr414Cys variant in PAH is a well-established pathogenic variant for PKU and has been reported in more than 25 individuals with PKU in a homozygous state or compound heterozygous state with another pathogenic variant (Okano 1991, Nie lsen 2010, Couce 2013). This variant led to reduced enzyme activity in in vitro studies (Okano 1991, Benit 1999, Zurfluh 2008). The p.Tyr414Cys variant has been identified in 0.05% (60/121,344) of chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs5030860) though this frequen cy is low enough to be consistent with a recessive carrier frequency. In summary , this variant meets our criteria to be classified as pathogenic for PKU in an a utosomal recessive manner based upon case observations and functional evidence. -

not provided

Pathogenic:7Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PAH: PM3:Very Strong, PM2, PP4, PS3:Supporting -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2021	This variant has been associated with marked decrease of PAH activity and at least mild PKU and BH4 responsiveness (PMIDs: 20063067(2010), 25596310 (2015), 30648773 (2019), and BIOPKU (http://www.biopku.org/)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 28, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Associated with tetrahydrobiopterin (BH4) responsiveness (PMID: 17935162); This variant is associated with the following publications: (PMID: 25750018, 10479481, 23500595, 20981092, 12655546, 24296287, 26919687, 26822130, 27469133, 15557004, 27121329, 26666653, 29030855, 34405919, 34828281, 15459954, 19609714, 18538294, 22975760, 22995991, 23559577, 20063067, 19036622, 21953985, 21228398, 26542770, 8889590, 12501224, 25087612, 26701937, 26503515, 26803807, 2014036, 14741196, 22526846, 22112818, 12655553, 11385716, 9450897, 8929956, 29499199, 30609409, 21871829, 9399896, 8556304, 30648773, 25596310, 30747360, 31980526, 31589614, 32668217, 33101986, 2044609, 34426522, 33375644, 32778825, 33465300, 29288420, 37421234, 36046396, 36699461, 36537053, 37443404, 17935162) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

PAH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2023

The PAH c.1241A>G variant is predicted to result in the amino acid substitution p.Tyr414Cys. This variant has been well documented to be causative for phenylalanine hydroxylase deficiency (Okano et al. 1991. PubMed ID: 2014036; Réblová et al. 2013. PubMed ID: 23357515). The p.Tyr414Cys substitution has been reported to reduce the activity of the PAH protein, with greatly varied estimates of residual activity ranging from ~10-80% of wild-type (Jennings et al. 2000. PubMed ID: 10980574; Couce et al. 2013. PubMed ID: 23500595; Danecka et al. 2015. PubMed ID: 25596310). The p.Tyr414Cys substitution has been reported to lead to a PAH protein that is responsive to BH4 (Zurflüh et al. 2008. PubMed ID: 17935162). This variant has been classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel and many other laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/593/). Nearly forty patients homozygous for the c.1241A>G (p.Tyr414Cys) variant have been reported in the BioPKU database; all of these patients presented with either mild hyperphenylalaninemia (MHPA) or mild phenylketonuria (PKU) (http://www.biopku.org). Based on these observations, we classify the c.1241A>G (p.Tyr414Cys) variant as pathogenic. -

Hyperphenylalaninemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2008

- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 20, 2021

ACMG categories: PS1,PM2,PM3,PP3,PP4,PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.31

D

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

26

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

D;D

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.82

D

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.96

D

MutationAssessor

Pathogenic

4.3

H;.

MutationTaster

Benign

1.0

A;A

PrimateAI

Uncertain

0.65

T

PROVEAN

Pathogenic

-8.1

D;D

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.98

MVP

0.99

MPC

0.26

ClinPred

0.94

D

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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: rs5030860; hg19: chr12-103234252;