rs5030850

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PP4PM3PVS1

This summary comes from the ClinGen Evidence Repository: PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4: Detected in 2 unrelated patients (PMID:1682234); PM3: Detected with H170D, pathogenic (PMID:11385716). 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, PP4, PM3). LINK:https://erepo.genome.network/evrepo/ui/classification/CA229757/MONDO:0009861/006

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

PAH
NM_000277.3 stop_gained

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:17O:1

Conservation

PhyloP100: 2.81

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.

PVS1

For more information check the summary or visit ClinGen Evidence Repository.

PM3

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.781C>T	p.Arg261Ter	stop_gained	7/13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2 linkuse as main transcript	c.781C>T	p.Arg261Ter	stop_gained	8/14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PAH	ENST00000553106.6 linkuse as main transcript	c.781C>T	p.Arg261Ter	stop_gained	7/13	1	NM_000277.3	ENSP00000448059	P1
PAH	ENST00000307000.7 linkuse as main transcript	c.766C>T	p.Arg256Ter	stop_gained	8/14	5		ENSP00000303500
PAH	ENST00000549247.6 linkuse as main transcript	n.540C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251334

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000288

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152100

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000456

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Phenylketonuria

Pathogenic:12

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1991	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Arg261X variant in PAH has been reported in >20 individuals with phenylketonuria in the homozygous or compound heterozygous state (Dworniczak 1991 PMID: 1682234, Yang 2001 PMID: 11385716, Liang 2014 PMID: 24401910, Gundorova 2018 PMID: 30067850). It has also been identified in 0.004% (3/68014) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on Aug 05, 2018 by the ClinGen-approved PAH Variant Curation expert panel (Variation ID 610). In vitro functional studies support an impact on protein function and have shown 1% residual enzyme activity (Zurfluh 2008 PMID: 17935162). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive phenylketonuria. ACMG/AMP Criteria applied: PVS_1, PM3, PM2_P, PS3_P. -
Pathogenic, criteria provided, single submitter	clinical testing	Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	Sep 19, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 27, 2024	- -
Pathogenic, reviewed by expert panel	curation	ClinGen PAH Variant Curation Expert Panel	Aug 05, 2018	PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4: Detected in 2 unrelated patients (PMID:1682234); PM3: Detected with H170D, pathogenic (PMID:11385716). 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, PP4, PM3). -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 11, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 21, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 03, 2023	This sequence change creates a premature translational stop signal (p.Arg261*) 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 (rs5030850, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with PAH-related conditions (PMID: 30067850). ClinVar contains an entry for this variant (Variation ID: 610). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	Aug 03, 2018	Variant summary: PAH c.781C>T (p.Arg261X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2.2e-05 in 277050 control chromosomes. c.781C>T has been reported in the literature in numerous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Zurfluh_2008). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -

not provided

Pathogenic:4Other:1

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	Nov 12, 2020	This nonsense variant causes the premature termination of PAH protein synthesis. In addition, it has been reported in multiple classic and mild PKU patients in the published literature (PMID: 16601866 (2006), 16755493 (2006), 19394257 (2009), 20920871 (2011), 22841515 (2012), 30067850 (2018)). Therefore, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 17, 2020	Functional analysis found that R261X is associated with significantly reduced enzyme activity (Zurflh et al., 2008; Ho et al., 2013); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); 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; Classified as not responsive to tetrahydrobiopterin (BH4) therapy (Zurflh et al., 2008); This variant is associated with the following publications: (PMID: 30747360, 25525159, 12655553, 10693064, 23500595, 17935162, 24401910, 1682234, 23532445, 28676969, 15503242, 19062537, 30067850, 29499199, 30221392, 31355225, 30275481, 31589614, 33101986) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 23, 2015	- -

Pulmonary hypertension, primary, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.63

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.94

MutationTaster

Benign

1.0

A;A

Vest4

0.93

GERP RS

3.8

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