rs76687508

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PP3PM2PP4_ModeratePS3PM3_Strong

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (0.00014) and gnomAD (0.0001301); PP3: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster; PP4_Moderate: Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup. (PMID:8222245; PMID:11142755); PM3_Strong: R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:11142755); PS3: In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote. (PMID:15319459; PMID:7915167). 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, PP4_Moderate, PM3_Strong, PS3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA273357/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

PAH
NM_000277.3 missense

Scores

10

5

4

Clinical Significance

Pathogenic reviewed by expert panel P:19O:1

Conservation

PhyloP100: 6.65

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:

PAH (HGNC:):

PAH 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.721C>T	p.Arg241Cys	missense_variant	7/13	ENST00000553106.6	NP_000268.1	P00439A0A024RBG4
PAH	NM_001354304.2 linkuse as main transcript	c.721C>T	p.Arg241Cys	missense_variant	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6 linkuse as main transcript	c.721C>T	p.Arg241Cys	missense_variant	7/13	1	NM_000277.3	ENSP00000448059.1		P00439
PAH	ENST00000307000.7 linkuse as main transcript	c.706C>T	p.Arg236Cys	missense_variant	8/14	5		ENSP00000303500.2		J3KND8
PAH	ENST00000549247.6 linkuse as main transcript	n.480C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

14

AN:

152082

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000774

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.000143

AC:

36

AN:

250956

Hom.:

0

AF XY:

0.000147

AC XY:

20

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00142

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000441

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

65

AN:

1461820

Hom.:

0

Cov.:

32

AF XY:

0.0000440

AC XY:

32

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000680

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000920

AC:

14

AN:

152200

Hom.:

0

Cov.:

32

AF XY:

0.0000941

AC XY:

7

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000776

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.0000444

Hom.:

0

Bravo

AF:

0.000147

ExAC

AF:

0.000140

AC:

17

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:13

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 02, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.014%). 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: 15319459 , 7915167). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.99). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 11142755). A different missense change at the same codon (p.Arg241His) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000102804). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 28, 2024	- -
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 in ExAC (0.00014) and gnomAD (0.0001301); PP3: Deleterious effect predicted in SIFT, PolyPhen2, MutationTaster; PP4_Moderate: Seen in multiple PKU patients. BH4 deficiency excluded in 2 patients. Upgraded per ClinGen Metabolic Workgroup. (PMID:8222245; PMID:11142755); PM3_Strong: R241C seen once in trans with R413P, and once with R243Q, both pathogenic. Upgraded per ClinGen SVI Workgroup. (PMID:11142755); PS3: In vitro PAH R241C mutant was found to have 25% PAH activity of normal. In vivo phenylalanine breath test measured a decreased level in R241C homozygote. (PMID:15319459; PMID:7915167). 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, PP4_Moderate, PM3_Strong, PS3). -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 241 of the PAH protein (p.Arg241Cys). This variant is present in population databases (rs76687508, gnomAD 0.1%). This missense change has been observed in individuals with PAH-related diseases (PMID: 8222245, 11486900, 14681498, 18985011, 19915519, 24368688, 26322415; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 102803). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PAH function (PMID: 16253218). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2016	Variant summary: The c.721C>T variant affects a conserved nucleotide, resulting in amino acid change from Arg to Cys located at catalytic domain of the protein. 5/5 in-silico tools predict this variant to be damaging. This variant was found in 17/120962 control chromosomes in the heterozygous state from the large and broad populations of ExAC at a frequency of 0.0001405, which does not exceed the maximal expected frequency of a pathogenic allele (0.0079057) in this gene. This variant is found in several patients with phenylketonuria with concordant recessive genotypes and is reported to be the most common mild pathogenic variant in the Taiwanese population. Functional studies are concordant with impairment of enzymatic activity. Multiple clinical laboratories have classified this variant as pathogenic. Taken together, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	research	Medical Laboratory Center, Huzhou Maternal and Child Health Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 09, 2016	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM3_VeryStrong+PP4_Moderate+PS3 -

not provided

Pathogenic:5Other:1

not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2022	Associated with mild hyperphenylalaninemia or mild phenylketonuria (PKU), although it has also been reported in an individual with classic PKU (Chien et al., 2004; Lee et al., 2008; Liang et al., 2014); R241C is associated with reduced residual PAH enzyme activity (Liang et al., 2014); 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: 11486900, 25750018, 9860305, 18985011, 9634518, 8222245, 14722928, 27264808, 29499199, 29317692, 11243094, 29961769, 30678510, 30747360, 30275481, 34426522, 33677757, 32668217, 32778825, 30037505, 17935162, 24401910, 31053953) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	PAH: PM3:Very Strong, PM2, PM5, PP3, PP4, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

PAH-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 12, 2024

The PAH c.721C>T variant is predicted to result in the amino acid substitution p.Arg241Cys. This variant has been reported in both the homozygous and compound heterozygous states in affected individuals and has been associated with mild hyperphenylalaninemia and mild phenylketonuria (e.g., Okano et al. 1994, PubMed ID: 7915167; Spaapen et al. 2001. PubMed ID: 11486900; Liang et al. 2014. PubMed ID: 24401910). This is a common pathogenic variant in the PAH gene, accounting for 1.5% of ~16,000 alleles documented in the PAHvdb (Hillert et al. 2020. PubMed ID: 32668217) and it is thought to be a founder variant in the Taiwanese population (Liang et al. 2014. PubMed ID: 24401910). The p.Arg241Cys amino acid change has been reported to decrease the activity of the PAH protein to roughly 25-50% of wild-type (Zurflüh et al. 2008. PubMed ID: 17935162; Liang et al. 2014. PubMed ID: 24401910). This variant is classified as pathogenic by multiple outside laboratories and the ClinGen PAH Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/102803). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.20

D

BayesDel_noAF

Pathogenic

0.48

CADD

Pathogenic

33

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Benign

0.78

T;T

M_CAP

Pathogenic

0.37

D

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Uncertain

2.2

M;.

PrimateAI

Pathogenic

0.87

D

PROVEAN

Uncertain

-2.5

D;D

REVEL

Pathogenic

0.86

Sift

Benign

0.043

D;D

Sift4G

Uncertain

0.048

D;D

Polyphen

1.0

D;.

Vest4

0.91

MVP

0.97

MPC

0.086

ClinPred

0.12

T

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.70

gMVP

0.93

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.

Other links and lift over

dbSNP: rs76687508; hg19: chr12-103246714; COSMIC: COSV61018094; COSMIC: COSV61018094;