ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1045T>C (p.Ser349Pro) (rs62508646)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078499 SCV000110355 pathogenic not provided 2018-01-15 criteria provided, single submitter clinical testing
GeneDx RCV000078499 SCV000239082 pathogenic not provided 2019-01-10 criteria provided, single submitter clinical testing The S349P variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The S349P missense variant is classified as a severe PAH pathogenic variant associated with a classic phenylketonuria (PKU) phenotype when homozygous or compound heterozygous with another severe PAH variant (Knappskog et al. 1995; Pey et al. 2007; Réblová et al. 2015; Jeannesson-Thivisol et al. 2015). Functional studies found that S349P is associated with null to very little residual enzyme activity (Knappskog et al. 1995; Pey et al. 2007; Couce et al. 2013). Furthermore, S349 is a buried residue located in the catalytic site of the phenylalanine hydroxylase protein (Réblová et al. 2015). The S349P variant is not responsive to BH4 therapy (Zurfluh et al., 2008).
Illumina Clinical Services Laboratory,Illumina RCV000000646 SCV000375564 pathogenic Phenylketonuria 2017-04-28 criteria provided, single submitter clinical testing Across a selection of the available literature, the PAH c.1045T>C (p.Ser349Pro) missense variant has been identified in a total of 41 individuals with phenylalanine hydroxylase deficiency, including in a homozygous state in four patients, in a compound heterozygous state in 39 patients, and in a heterozygous state in one patient (Forrest et al. 1991; John et al. 1992; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996; Vela-Amieva et al. 2015; Aldámiz-Echevarría et al. 2016). The variant was also identified in an additional eight alleles of unknown zygosity (Zurflüh et al. 2008; Couce et al. 2013). The p.Ser349Pro variant was absent from 152 control individuals but is reported at an allele frequency of 0.00005 in the European (non-Finnish) population of the Exome Aggregation Consortium. The p.Ser349Pro variant is associated with a severe phenotype and results in significantly reduced PAH activity levels of between 0% and 1.2%, and immunoreactivity levels of between 0% and 2.0% compared to wild type (Forrest et al. 1991; Weinstein et al. 1993; Knappskog et al. 1995; Romano et al. 1996). Based on the collective evidence, the p.Ser349Pro 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.
Fulgent Genetics,Fulgent Genetics RCV000000646 SCV000611227 pathogenic Phenylketonuria 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000000646 SCV000629169 pathogenic Phenylketonuria 2019-09-13 criteria provided, single submitter clinical testing This sequence change replaces serine with proline at codon 349 of the PAH protein (p.Ser349Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. This variant is present in population databases (rs62508646, ExAC 0.009%). This variant has been reported in individuals affected with mild or classic phenylketonuria, atypical phenylketonuria and hyperphenylalaninemia (PMID: 7860062, 8268925, 8659548, 9399896, 9781015, 10479481, 17096675, 17935162, 18294361, 2063869, 23500595, 23514811). Some individuals reported with phenylketonuria were homozygous for this variant. ClinVar contains an entry for this variant (Variation ID: 615). Experimental studies have shown that this missense change reduced the relative residual enzyme activity to 0-2% compared to wide type (PMID: 7860062, 8095248, 23500595, 17935162). A different missense substitution at this codon (p.Ser349Ala) has been determined to be pathogenic and has been reported in individuals affected with phenylketonuria (PMID: 16256386, 26666653, 24705691). The Ser349 codon is located in the active site of the PAH protein and this residue contains a chemical group that is important for intramolecular contacts within the enzyme's active site (PMID: 26666653). This suggests that the serine residue is critical for PAH protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Myriad Women's Health, Inc. RCV000000646 SCV001193874 likely pathogenic Phenylketonuria 2019-12-20 criteria provided, single submitter clinical testing NM_000277.1(PAH):c.1045T>C(S349P) is classified as likely pathogenic in the context of phenylalanine hydroxylase deficiency. Sources cited for classification include the following: PMID 22513348, 8095248, 1301193, 21953985 and 17935162. Classification of NM_000277.1(PAH):c.1045T>C(S349P) is based on the following criteria: There is strong evidence of association with the variant and the relevant disease and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening.
Integrated Genetics/Laboratory Corporation of America RCV000000646 SCV001363423 pathogenic Phenylketonuria 2019-01-28 criteria provided, single submitter clinical testing Variant summary: PAH c.1045T>C (p.Ser349Pro) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 276958 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (6.1e-05 vs 0.0079), allowing no conclusion about variant significance. c.1045T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (se e.g. Bueno 2013, Couce 2013). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, concluding that the most pronounced variant effect results in ~1% of normal activity (see e.g. Bueno 2013, Zurfluh 2008). Six 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000646 SCV000020796 pathogenic Phenylketonuria 1995-02-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078499 SCV000119302 not provided not provided no assertion provided not provided

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