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rs5030857

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4

The NM_000277(PAH):c.1208C>T(p.Ala403Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000578 in 152126 control chromosomes in the gnomAD Genomes database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.00058 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00060 ( 0 hom. )

Consequence

PAH
NM_000277 missense

Scores

8
6
5

Clinical Significance

Pathogenic reviewed by expert panel P:33U:1O:1

Conservation

PhyloP100: 7.70

Links

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
?
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000277
PP3
?
Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
PP5
?
Variant 12:102840507-G>A is Pathogenic according to our data. Variant chr12-102840507-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 92731. Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr12-102840507-G-A is described in Lovd as [Pathogenic]. Variant chr12-102840507-G-A is described in Lovd as [Pathogenic].
BP4
?
Computational evidence support a benign effect (MetaRNN=0.15398467).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PAHNM_000277.3 linkuse as main transcriptc.1208C>T p.Ala403Val missense_variant 12/13 ENST00000553106.6
PAHNM_001354304.2 linkuse as main transcriptc.1208C>T p.Ala403Val missense_variant 13/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PAHENST00000553106.6 linkuse as main transcriptc.1208C>T p.Ala403Val missense_variant 12/131 NM_000277.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000578
AC:
88
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.00692
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000764
Gnomad OTH
AF:
0.00191
GnomAD3 exomes
AF:
0.000601
AC:
151
AN:
251414
Hom.:
0
AF XY:
0.000618
AC XY:
84
AN XY:
135876
show subpopulations
Gnomad AFR exome
AF:
0.0000615
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00506
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000765
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000476
AC:
695
AN:
1460642
Hom.:
3
AF XY:
0.000493
AC XY:
358
AN XY:
726680
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000224
Gnomad4 ASJ exome
AF:
0.00494
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000446
Gnomad4 OTH exome
AF:
0.000663
Alfa
AF:
0.000924
Hom.:
0
Bravo
AF:
0.000612
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000581
AC:
5
ExAC
AF:
0.000535
AC:
65
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00213
EpiControl
AF:
0.00160

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:33Uncertain:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Phenylketonuria Pathogenic:24Uncertain:1
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease CompanyAug 30, 2021- -
Pathogenic, reviewed by expert panelcurationClinGen PAH Variant Curation Expert PanelAug 10, 2018PAH-specific ACMG/AMP criteria applied: PP4_Moderate: Seen on 3 PKU alleles, BH4 deficiency was ruled out. Upgraded per ClinGen Metabolic WG. (PMID:8268925); PM3_VeryStrong: A403V found with 4 pathogenic variants . Upgraded per ClinGen SVI workgroup. (PMID:9429153); PS3: In vitro A403V mutant protein activity was ~43% wt. (PMID:21820508). 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: (PP4_Moderate, PM3_VeryStrong, PS3). -
Pathogenic, criteria provided, single submitterclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversityApr 05, 2016The c.1208C>T (p.Ala403Val) missense variant in the PAH gene is a well-established pathogenic variant associated with mild hyperphenylalaninemia and BH4-responsive phenylketonuria (Aulehla-Scholz et al., 2003; Fiori et al., 2005; Daniele et al., 2007; Zurflüh et al., 2008). Multiple in vitro functional studies have demonstrated that this variant results in reduced enzymatic activity to approximately 32% (Bénit et al., 1999; Blau et al., 2002; Cerreto et al., 2011). This variant is reported at low frequency in the population databases (Exome Sequencing Project = 0.058%; 1000 Genomes = 0.2%; and ExAC = 0.0.093%). Multiple in silico algorithms predict this variant to have a deleterious effect (GERP = 5.63; CADD = 26.8; PolyPhen = 0.996). Multiple reputable diagnostic laboratories have reported this variant as a well-established pathogenic variant (Emory Genetics Laboratory, Partners HealthCare Personalized Medicine, and GeneDx). Therefore, this collective evidence supports the classification of the c.1208C>T (p.Ala403Val) as a Pathogenic variant for Phenylketonuria. We have confirmed this finding in our laboratory using Sanger sequencing. -
Pathogenic, criteria provided, single submitterclinical testingPerkinElmer GenomicsApr 05, 2022- -
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineSep 30, 2014The p.Ala403Val variant in PAH is a well-established pathogenic variant for phen ylketonuria (PKU) and is associated with a milder phenotype (Zekanowski 1997, Be nit 1999, Bardelli 2002, Kasnauskiene 2002, Daniele 2007, Groselj 2012, Georgiou 2012, Bik-Multanowski 2013, Polak 2013). This variant has been identified in 0. 5% (51/10150) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, the p.Ala403Val variant in PAH meets cr iteria to be classified as pathogenic for PKU in an autosomal recessive manner. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 17, 2016Variant summary: The c.1208C>T variant affects a conserved nucleotide, resulting in amino acid change from Ala to Val. 4/5 in-silico tools predict this variant to be damaging. This variant is found in 65/121306 control chromosomes at a frequency of 0.0005358, which does not exceed maximal expected frequency of a pathogenic allele (0.0079057). This variant was one of the most common pathogenic variant found in European PKU or MHP patients. The phenotype of these patients is likely to be mild and they respond to BH4 treatment. Two independent groups showed PAH p.A403V activity is 30-40%, which is consistant with the mild phenotype seen in the patients carrying this variant. In addition, multiple clinical laboratories/reputable databases/literatures classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingAl Jalila Children's Genomics Center, Al Jalila Childrens Speciality HospitalNov 15, 2020- -
Pathogenic, criteria provided, single submitterclinical testingBaylor Genetics-- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Pathogenic, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, University Medical Center UtrechtOct 08, 2014- -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteAug 28, 2019A heterozygous missense variant was identified, NM_000277.2(PAH):c.1208C>T in exon 12 of 13 of the PAH gene. This substitution is predicted to create a minor amino acid change from alanine to valine at position 403 of the protein, NP_000268.1(PAH):p.(Ala403Val). The alanine at this position has high conservation (100 vertebrates, UCSC), and is located within the biopterin hydroxylase domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.06%% (164 heterozygotes, 0 homozygotes). The variant has previously been reported as pathogenic in patients with mild hyperphenylalaninemia and mild phenylketonuria (ClinVar, Jeannesson-Thivol E. et al. 2015). In addition, functional studies show that this variant results in approximately 43% residual activity compared to wild-type (Cerreto M. et al. 2011). Based on information available at the time of curation, this variant has been classified as PATHOGENIC. -
Pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Dec 14, 2019NM_000277.1(PAH):c.1208C>T(A403V) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and can be associated with variant or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 23430547, 18299955, 17096675, 22513348, 23792259, 16198137, 17935162, 19062537, 24350308 and 22526846. Classification of NM_000277.1(PAH):c.1208C>T(A403V) 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, no assertion criteria providedclinical testingClinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)Apr 01, 2023- -
Pathogenic, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Pathogenic, no assertion criteria providedresearchDivision of Human Genetics, Children's Hospital of PhiladelphiaSep 23, 2015- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabJul 22, 2021- -
Pathogenic, criteria provided, single submitterclinical testingIntergen, Intergen Genetics and Rare Diseases Diagnosis CenterJun 08, 2023- -
Pathogenic, criteria provided, single submitterclinical testingNew York Genome CenterAug 12, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterJan 01, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Klinikum rechts der IsarMay 16, 2022- -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 09, 2019The PAH c.1208C>T (p.Ala403Val) missense variant is well-described as a pathogenic mild, BH4-responsive variant. Across a selection of the available literature, the p.Ala403Val variant has been identified in affected individuals of various ethnic origins including in six in a homozygous state, in 91 in a compound heterozygous state and in one in a heterozygous state (Spaapen et al. 2001; Desviat et al. 2001; Aulehla-Scholz et al. 2003; Zurflüh et al. 2008; Kasnauskiene et al. 2008; Sterl et al. 2013; Djordjevic et al. 2013; Couce et al. 2013; Trunzo et al. 2013; Bik-Multanowski et al. 2013). The p.Ala403Val was reported in two of 320 controls and is reported at a frequency of 0.005112 in the Ashkenazi Jewish population of the Genome Aggregation Database. The Ala403 residue is highly conserved. Functional studies demonstrated that the p.Ala403Val variant resulted in residual PAH enzyme activity between 12% and 32% of wild type (Zurflühet al. 2008; Danecka et al. 2015). Based on the collective evidence the p.Ala403Val 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 submitterclinical testingInvitaeNov 04, 2022This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 403 of the PAH protein (p.Ala403Val). This variant is present in population databases (rs5030857, gnomAD 0.5%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with BH4-responsive mild hyperphenylalaninemia (HPA), mild form of phenylketonuria, and/or non-PKU HPA (PMID: 2575001, 8268925, 8739972, 8830172, 9429153, 17096675, 25596310). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spanish, Italian, or Israeli ancestry (PMID: 8268925, 8739972, 8830172, 9429153, 25596310). ClinVar contains an entry for this variant (Variation ID: 92731). 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. Experimental studies have shown that this missense change affects PAH function (PMID: 21820508, 23500595, 23559577). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn-- -
not provided Pathogenic:8Other:1
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 26, 2017- -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2023Criteria applied: PM3:Very Strong, PM2, PP4:Moderate, PS3:Moderate -
Pathogenic, no assertion criteria providedclinical testingDepartment of Pathology and Laboratory Medicine, Sinai Health System-The PAH p.Ala403Val variant has been reported in multiple individuals with Phenylketonuria (PKU) from Italian, Argentine, Slovak, French, Russian and Israeli backgrounds; this variant is generally associated with a mild phenotype, as well as non-PKU mild hyperphenylalaninemia in one homozygote (Gundorova_2019_PMID:30668579, Jeannesson-Thivisol_2015_PMID:26666653, Bercovich_2008_PMID:18299955, Bardelli_2002_PMID:12409276 , Polak_2013_PMID:23764561, Enacan_2019, Daniele_2009_PMID_19292873). The variant was identified in dbSNP (ID: rs5030857) and ClinVar (classified as pathogenic for Phenylketonuria by ClinGen PAH Variant Curation Expert Panel, Laboratory for Molecular Medicine, Invitae and 12 other laboratories). The variant was identified in control databases in 164 of 282804 chromosomes at a frequency of 0.0005799 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 53 of 10368 chromosomes (freq: 0.005112), European (non-Finnish) in 96 of 129168 chromosomes (freq: 0.000743), Other in 3 of 7228 chromosomes (freq: 0.000415), Latino in 8 of 35394 chromosomes (freq: 0.000226), African in 3 of 24958 chromosomes (freq: 0.00012) and South Asian in 1 of 30614 chromosomes (freq: 0.000033), but was not observed in the East Asian or European (Finnish) populations. The p.Ala403 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. Functional studies of the p.A403V variant have demonstrated reduced enzyme activity (only 43±4% of wild-type enzyme activity), altered oligomerization and lower inferred melting temperatures compared to the wild type protein indicating a loss in stability (Cerreto_2011_PMID:21820508). There is also evidence that patients with this variant would likely respond to BH4, a compound that helps convert phenylalanine to other essential molecules in the body (Cerreto_2011_PMID:21820508; Daniele_2008_PMID:18346471; Gundorova_2019_PMID:30668579; Bardelli_2002_PMID:12409276; Polak_2013_PMID:23764561). In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
not provided, no assertion providedliterature onlyDeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE-- -
Pathogenic, criteria provided, single submitterclinical testingAiLife Diagnostics, AiLife DiagnosticsJan 25, 2022- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 14, 2020Associated with mild hyperphenylalaninemia and 30-40% residual phenylalanine hydroxylase enzyme activity (Bnit et al., 1999); 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: 31980526, 30747360, 27121329, 25596310, 30487145, 30667134, 30037505, 29499199, 8268925, 28956315, 25750018, 17935162, 12409276, 27469133, 27830119, 27175728, 23942198, 12501224, 8889590, 15557004, 23764561, 24033266, 17096675, 12640344, 22330942, 22513348, 25087612, 23500595, 23430547, 23559577, 21953985, 21820508, 12644360, 11486900, 10479481, 8739972, 18346471, 22526846, 23792259, 16051511, 18482855, 9686365, 9298832, 18299955, 11096279, 9429153, 10598814) -
Pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoNov 12, 2020In the published literature, it has been reported along with a second pathogenic variant in multiple individuals affected with BH4-responsive mild hyperphenylalaninemia (PMID: 8739972 (1996), 8889590 (1996), 21820508 (2011), 23430547 (2013), 25596310 (2015)). Functional studies have shown this variant has reduced enzyme activity (PMID: 10479481 (1999), 21820508 (2011), 30037505 (2018)). Furthermore, the variant is associated with BH4-responsiveness (PMID: 16290003 (2005), 21820508 (2011)). Therefore, the variant is classified as pathogenic. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 21, 2022The c.1208C>T (p.A403V) alteration is located in coding exon 12 of the PAH gene. This alteration results from a C to T substitution at nucleotide position 1208, causing the alanine (A) at amino acid position 403 to be replaced by a valine (V). Based on data from gnomAD, the T allele has an overall frequency of 0.06% (164/282804) total alleles studied. The highest observed frequency was 0.51% (53/10368) of Ashkenazi Jewish alleles. The c.1208C>T (p.A403V) alteration has been detected in the homozygous state, and in conjunction with another alteration in PAH , in multiple individuals with phenylalanine hydroxylase deficiency and is primarily associated with mild hyperphenylalaninemia phenotypes (Guldberg, 1993; Zekanowski, 1997; Benit, 1999; Aulehla-Scholz, 2003; Daniele, 2007; Berkovich, 2008; Couce, 2013; Aldámiz-Echevarría, 2016). In addition, clinical studies have indicated that this is a BH4-responsive allele (Zurfluh, 2008; Aldámiz-Echevarría, 2016). This amino acid position is highly conserved in available vertebrate species. Functional studies have demonstrated a significant reduction in enzymatic activity for the A403V variant (Benit, 1999; Blau, 2004; Cerreto, 2011; Himmelreich, 2018). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.32
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Pathogenic
0.47
Cadd
Pathogenic
27
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;D
Eigen
Pathogenic
0.81
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Pathogenic
0.35
D
MetaRNN
Benign
0.15
T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-3.2
D;D
REVEL
Pathogenic
0.92
Sift
Benign
0.12
T;T
Sift4G
Benign
0.23
T;T
Polyphen
1.0
D;.
Vest4
0.84
MVP
0.99
MPC
0.23
ClinPred
0.13
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.79
gMVP
0.87

Splicing

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: rs5030857; hg19: chr12-103234285; COSMIC: COSV61020906; COSMIC: COSV61020906;