rs5030846

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000277.3(PAH):c.727C>T(p.Arg243Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000998 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

PAH
NM_000277.3 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:17O:1

Conservation

PhyloP100: 8.10

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 12-102852930-G-A is Pathogenic according to our data. Variant chr12-102852930-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 588.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102852930-G-A is described in Lovd as [Pathogenic]. Variant chr12-102852930-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAH	NM_000277.3 linkuse as main transcript	c.727C>T	p.Arg243Ter	stop_gained	7/13	ENST00000553106.6
PAH	NM_001354304.2 linkuse as main transcript	c.727C>T	p.Arg243Ter	stop_gained	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.727C>T	p.Arg243Ter	stop_gained	7/13	1	NM_000277.3	P1
PAH	ENST00000307000.7 linkuse as main transcript	c.712C>T	p.Arg238Ter	stop_gained	8/14	5
PAH	ENST00000549247.6 linkuse as main transcript	n.486C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251076

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000970

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000106

AC:

155

AN:

1461846

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000133

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change creates a premature translational stop signal (p.Arg243*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs5030846, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with PKU (PMID: 2014036, 11486900, 14741196, 17935162, 23500595, 24130151, 26666653; Invitae). ClinVar contains an entry for this variant (Variation ID: 588). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 29, 2023	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 07, 2018	PAH-specific ACMG/AMP criteria applied: PVS1: nonsense variant; PS3: <1% of normal PAH activity (PMID:2014036). 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: (PVS1, PS3). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 15, 1991	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The PAH c.727C>T (p.Arg243Ter) variant is a stop gained variant that is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Arg243Ter variant has been identified in a total of 20 patients with phenylalanine hydroxylase deficiency leading to phenylketonuria, including in ten in a homozygous state and in ten in a compound heterozygous state (Wang et al. 1990; Ramus et al. 1993; ZurflÃ¼h et al. 2008; Zare-Karizi et al. 2011; Spaapen et al. 2011; Couce et al. 2013; Bashyam et al. 2014). Control data are unavailable for this variant from these studies, which is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. Patients with the p.Arg243Ter variant showed reduced enzyme activity of < 1% of wild type (ZurflÃ¼h et al. 2008; Couce et al. 2013). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg243Ter variant is classified as pathogenic for phenylalanine hydroxylase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 02, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2017	Variant summary: The PAH c.727C>T (p.Arg243X) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One truncation downstream of this position has been classified as pathogenic by our laboratory (c.1089delG, p.Lys363fsX37). One in silico tool predicts a damaging outcome for this variant. A functional study found this variant to be associated with in vitro hydroxylase activity <1% of normal levels (Okano_1991). This variant was found in the large control database ExAC in 6/121162 control chromosomes at a frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported in many affected individuals with phenylketonuria and hyperphenylalaninemia (Zurfluh_2008, Couce_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided

Pathogenic:6Other:1

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2013	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
not provided, no classification provided	literature only	DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2019	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Patients homozygous for the R243X variant are reported to have a classic PKU phenotype and are not responsive to BH4 therapy (Zurfluh et al., 2008); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 25525159, 26589311, 26210745, 30747360, 26655635, 23500595, 11486900, 24941924, 24130151, 17935162, 26759449, 27121329, 14741196, 2309142, 2014036, 28676969, 28540274, 29499199, 31355225, 26666653, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2020	- -

PAH-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 23, 2023

The PAH c.727C>T variant is predicted to result in premature protein termination (p.Arg243*). This sequence variant has been reported to be causative phenylalanine hydroxylase deficiency and has been associated with classical phenylketonuria (PKU) (e.g., Okano et al. 1991. PubMed ID: 2014036; Couce et al. 2013. PubMed ID: 23500595; Jeannesson-Thivisol et al. 2015. PubMed ID: 26666653). Patients with the c.727C>T variant have been reported to be non-responsive to tetrahydrobiopterin (BH4) (Zurflüh et al. 2008. PubMed ID: 17935162). Nearly one hundred patients homozygous for the c.727C>T (p.Arg243*) variant have been reported in the BioPKU database; all of these patients presented with classic PKU (http://www.biopku.org). In the ClinVar database, this variant is classified as pathogenic by the ClinGen PAH Variant Curation Expert Panel as well as multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/588/). Nonsense variants in PAH are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2021

The c.727C>T (p.R243*) alteration, located in exon 7 (coding exon 7) of the PAH gene, consists of a C to T substitution at nucleotide position 727. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 243. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This mutation has been reported in multiple homozygous and compound heterozygous individuals with phenylalanine hydroxylase deficiency (Zare-Karizi, 2011; Couce, 2013; Aldámiz-Echevarría, 2016; Su, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.63

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A

Vest4

0.95

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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