ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1208C>T (p.Ala403Val) (rs5030857)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000150075 SCV000852096 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-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).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078506 SCV000110362 pathogenic not provided 2017-04-26 criteria provided, single submitter clinical testing
GeneDx RCV000078506 SCV000239092 pathogenic not provided 2020-10-14 criteria provided, single submitter clinical testing Associated 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)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150075 SCV000245646 pathogenic Phenylketonuria 2014-09-30 criteria provided, single submitter clinical testing The 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, 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000150075 SCV000494231 pathogenic Phenylketonuria 2016-04-05 criteria provided, single submitter clinical testing The 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.
Invitae RCV000150075 SCV000629180 pathogenic Phenylketonuria 2020-11-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 403 of the PAH protein (p.Ala403Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs5030857, ExAC 0.09%). This variant is the most prevalent PAH variant identified among individuals with mild hyperphenylalaninemia (HPA) in Spain, Italy and Israel (PMID: 8268925, 8739972, 8830172, 9429153, 25596310). This variant is also the most common BH4-responsive variant seen in affected individuals (PMID: 17935162). It has been found as homozygous in individuals affected with non-PKU HPA and in a few instances with a mild form of phenylketonuria (PKU) (PMID: 17096675, 25750018). ClinVar contains an entry for this variant (Variation ID: 92731). Experimental studies have shown that this missense change affects the oligomerization of the PAH subunits into a a functionally active tetramer and results in a mildly reduced enzymatic activity (PMID: 21820508, 23500595, 23559577). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000150075 SCV000696431 pathogenic Phenylketonuria 2016-03-17 criteria provided, single submitter clinical testing Variant 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.
Ambry Genetics RCV000622360 SCV000742984 pathogenic Inborn genetic diseases 2014-09-07 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000150075 SCV000744091 pathogenic Phenylketonuria 2014-10-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000150075 SCV000893265 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000150075 SCV000914553 pathogenic Phenylketonuria 2019-01-09 criteria provided, single submitter clinical testing The 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.
Mendelics RCV000150075 SCV001138797 pathogenic Phenylketonuria 2019-05-28 criteria provided, single submitter clinical testing
Baylor Genetics RCV000150075 SCV001163711 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000150075 SCV001193782 pathogenic Phenylketonuria 2019-12-14 criteria provided, single submitter clinical testing NM_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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078506 SCV001247321 pathogenic not provided 2020-11-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000150075 SCV001439914 uncertain significance Phenylketonuria 2019-01-01 criteria provided, single submitter clinical testing
Nilou-Genome Lab RCV000150075 SCV001810541 pathogenic Phenylketonuria 2021-07-22 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078506 SCV000119389 not provided not provided no assertion provided not provided
Division of Human Genetics,Children's Hospital of Philadelphia RCV000150075 SCV000536715 pathogenic Phenylketonuria 2015-09-23 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000150075 SCV000733122 pathogenic Phenylketonuria no assertion criteria provided clinical testing
Natera, Inc. RCV000150075 SCV001463114 pathogenic Phenylketonuria 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000078506 SCV001552550 pathogenic not provided no assertion criteria provided clinical testing 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000078506 SCV001808837 pathogenic not provided no assertion criteria provided clinical testing

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