ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.898G>T (p.Ala300Ser) (rs5030853)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000150084 SCV000852126 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PP3: Deleterious in SIFT, Polyphen2, MutationTaster; PP4_Moderate: A300S found on 56/588 hyperphenylalaninemic patients, BH4 deficiency excluded. Upgraded per ClinGen Metabolic WG. (PMID:21147011); PM3_VeryStrong: Detected with c.1066-11G>A (P), R261Q(P/LP), L48S (P), R176X (P) in 20 patients. (PMID:21147011); PS3: A300S in vitro PAH activity of 31% (PMID:17935162). 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: (PP3, PP4_Moderate, PM3_VeryStrong, PS3).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078536 SCV000110392 pathogenic not provided 2017-06-16 criteria provided, single submitter clinical testing
GeneDx RCV000078536 SCV000239078 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing The A300S variant in the PAH gene has been reported previously as a mild PAH variant associated with mild hyperphenylalaninemia or mild PKU (Danecka et al., 2015; Jeannesson-Thivisol et al., 2015). This variant is associated with 31% residual enzyme activity (Zurfluh et al. 2008). The A300S variant has been associated with BH4 responsiveness (Zurfluh et al. 2008; Heintz et al., 2013; Jeannesson-Thivisol et al., 2015). The A300S variant is observed in 48/66582 (0.07%) alleles from individuals of non-Finnish European background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The A300S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. Missense variants at the same codon (A300V) and in nearby residues (R297C, R297H, R297L, F299C, Q301P, Q301H, S303P, S303A) have been reported in the Human Gene Mutation Database in association with PAH-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, we interpret A300S as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000150084 SCV000375565 pathogenic Phenylketonuria 2016-06-14 criteria provided, single submitter clinical testing The c.898G>A (p.Ala300Ser) variant is well-documented in the literature and is associated with mild phenylketonuria phenotype that is responsive to BH4 treatment. Across a selection of available literature, the p.Ala300Ser variant has been identified in a homozygous state in at least two patients, in a compound heterozygous state in at least 20 patients, and in 40 patients whose zygosity was not explicitly stated but are presumed to be compound heterozygous (Eisensmith et al. 1992; Spaapen et al. 2001; Blau and Erlandsen 2004; Zurflüh et al. 2008; Bercovich et al. 2008; Couce et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00072 in the European (Non-Finnish) population of the Exome Aggregation Consortium. Functional studies showed that the p.Ala300Ser variant did not affect enzyme activity, but resulted in severe misfolding and destabilization of the PAH protein (Gersting et al. 2008). Based on the collective evidence, the p.Ala300Ser variant is classified as pathogenic for phenylalanine hydroxylase deficiency.
Fulgent Genetics,Fulgent Genetics RCV000150084 SCV000611236 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000150084 SCV000629225 pathogenic Phenylketonuria 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 300 of the PAH protein (p.Ala300Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is present in population databases (rs5030853, ExAC 0.07%). This variant is a prevalent mutation in European populations and has been reported in multiple individuals affected with PAH deficiency-related diseases (PMID: 25596310, 22330942, 23764561, 25155776, 27682710). ClinVar contains an entry for this variant (Variation ID: 92751). Experimental studies have shown that this missense change affects enzyme stability and causes partial reduction of enzyme activity in vitro (PMID: 17935162, 25596310, 15557004, 18538294, 26803807). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000590551 SCV000696470 pathogenic Hyperphenylalaninemia, non-pku 2016-06-09 criteria provided, single submitter clinical testing Variant summary: The PAH c.898G>T (p.Ala300Ser) variant involves the alteration of a conserved nucleotide within the catalytic domain. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 54/121010 control chromosomes at a frequency of 0.0004462, which does not exceed the estimated maximal expected allele frequency of a pathogenic PAH variant (0.0079057). This variant has been reported as one of the most common pathogenic variants that associate with a milder phenotype, which is consistant with the finding that p.Ala300Ser retains 31% of enzyme activity (Zurfluh_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000078536 SCV000889565 pathogenic not provided 2016-10-04 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000150084 SCV000967677 pathogenic Phenylketonuria 2018-07-17 criteria provided, single submitter clinical testing The p.Ala300Ser variant in PAH is a well-established pathogenic variant in patie nts with phenylketonuria (Trefz 2009, Heintz 2013, Danecka 2015), and is frequen tly associated with milder course and responsiveness to BH4 (Trefz 2009, Heintz 2013). In vitro functional studies provide some evidence that the p.Ala300Ser va riant impacts protein function (Shen 2016). This variant has been identified in 0.6% (67/10130) of Ashkenazi Jewish chromosomes by the Genome Aggregation Databa se (gnomAD,; dbSNP rs5030853). Although this va riant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools a nd conservation analysis suggest that the p.Ala300Ser variant may impact the pro tein, though this information is not predictive enough to determine pathogenicit y. In summary, this variant meets criteria to be classified as pathogenic for ph enylketonuria in an autosomal recessive manner. ACMG/AMP Criteria applied PS3; P S4; PP3
Baylor Genetics RCV000150084 SCV001163717 pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000150084 SCV001194112 pathogenic Phenylketonuria 2019-12-26 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.898G>T(A300S) is classified as pathogenic in the context of phenylalanine hydroxylase deficiency and may be associated with classic, variant, or non-PKU hyperphenylalaninemia. Sources cited for classification include the following: PMID 9298832, 18538294, 23500595, 18299955, 16198137, 21147011, 15557004, 23792259, 24350308, and 17935162. Classification of NM_000277.1(PAH):c.898G>T(A300S) 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 RCV000078536 SCV001249175 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000150084 SCV001251825 pathogenic Phenylketonuria 2020-05-03 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001196619 SCV001367227 pathogenic Global developmental delay; Delayed speech and language development; Synophrys; Low anterior hairline; Central hypotonia 2019-07-30 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PM3. This variant was detected in heterozygous state.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197621 SCV001368400 pathogenic Seizures; Optic atrophy; Amblyopia; Neonatal asphyxia; Epileptic encephalopathy 2019-11-13 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this varinat's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3. This variant was detected in heterozygous state.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078536 SCV000119761 not provided not provided no assertion provided not provided
GenomeConnect, ClinGen RCV000150084 SCV000840271 not provided Phenylketonuria no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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