rs5030846

Variant names:

• chr12-102852930-G-A
• rs5030846
• NM_000277.3:c.727C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-102852930-G-A
• chr12-102852930-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PVS1

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA220585/MONDO:0009861/006

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PAH NM_000277.3 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:22 O:1
• Conservation: PhyloP100: 8.10
• Publications: 48 publications found

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 Gene-Disease associations (from GenCC):

• phenylketonuria

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Myriad Women’s Health
• classic phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• maternal phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild hyperphenylalaninemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mild phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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	c.727C>T	p.Arg243*	stop_gained	Exon 7 of 13	ENST00000553106.6	NP_000268.1
PAH	NM_001354304.2	c.727C>T	p.Arg243*	stop_gained	Exon 8 of 14		NP_001341233.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAH	ENST00000553106.6	c.727C>T	p.Arg243*	stop_gained	Exon 7 of 13	1	NM_000277.3	ENSP00000448059.1
PAH	ENST00000307000.7	c.712C>T	p.Arg238*	stop_gained	Exon 8 of 14	5		ENSP00000303500.2
PAH	ENST00000549247.6	n.486C>T		non_coding_transcript_exon_variant	Exon 1 of 6	2
PAH	ENST00000635477.1	c.-114C>T		upstream_gene_variant		5		ENSP00000489230.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152106 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.0000438 AC: 11 AN: 251076 AF XY: 0.0000442

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 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.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 78 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000133 AC: 148 AN: 1111986

Other (OTH) AF: 0.000116 AC: 7 AN: 60394

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74294

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000128 Hom.: 0

Bravo AF: 0.0000529

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Phenylketonuria Pathogenic:11

Aug 22, 2017

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.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. -

Mar 15, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1+PM2_Supporting+PM3_VeryStrong -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 08, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with phenylketonuria (MIM#261600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (13 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is classified as pathogenic by an expert panel in ClinVar and has been observed as homozygous or compound heterozygous in individuals with classical PKU (PMID: 26666653). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). ClinVar contains an entry for this variant (Variation ID: 588). For these reasons, this variant has been classified as Pathogenic. -

Mar 16, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Zurflüh 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 (Zurflüh 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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 07, 2018

ClinGen PAH Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

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). -

Jan 02, 2014

Counsyl

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided Pathogenic:8 Other:1

Dec 05, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 20, 2013

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_moderate, PM3, PS3, PVS1 -

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 30, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PAH c.727C>T (p.Arg243*) variant causes the premature termination of PAH protein synthesis. In the published literature, this variant has been reported in individuals with phenylketonuria (PKU) and is associated with having nearly absent residual PAH activity (PMIDs: 31355225 (2019), 26666653 (2015), 24130151 (2014), 23500595 (2013), 17935162 (2008), 15589814 (2004), 14741196 (2004), 11486900 (2001), 2014036 (1991)). BH4-reponsiveness of this variant ranged from mildly responsive (PMIDs: 15589814 (2004), 14741196 (2004)) to nonresponsive (PMIDs: 26666653 (2015), 17935162 (2008)). The frequency of this variant in the general population, 0.000085 (11/128860 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PAH-related disorder Pathogenic:1

Jul 16, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Apr 20, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Ald&aacute;miz-Echevarr&iacute;a, 2016; Su, 2019). Based on the available evidence, this alteration is classified as pathogenic. -

Hyperphenylalaninemia Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1, PS3,PM2,PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		8.1
Vest4		0.95
GERP RS		3.0
PromoterAI		-0.034	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs5030846; hg19: chr12-103246708; COSMIC: COSV61015179; COSMIC: COSV61015179;