ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.638T>C (p.Leu213Pro) (rs62516109)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000150086 SCV000852093 pathogenic Phenylketonuria 2018-10-01 reviewed by expert panel curation The c.638T>C (p.Leu213Pro) variant in PAH has been reported in in 4 patients with PAH deficiency (BH4 deficiency excluded). (PP4_Moderate; PMID: 8659548; PMID: 19292873; PMID: 21147011). This variant is absent from large population studies (PM2; This variant was detected in trans with c.1066-11G>A, E390G, D415N, R261X.(Pathogenic in ClinVar) (PM3_Very-strong; PMID: 19292873; PMID: 21147011; PMID: 8632937). Computational prediction tools and conservation analysis suggest that the c.638T>C variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM3_Very-strong
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078527 SCV000110383 pathogenic not provided 2012-08-14 criteria provided, single submitter clinical testing
Counsyl RCV000150086 SCV000220516 likely pathogenic Phenylketonuria 2014-07-18 criteria provided, single submitter literature only
GeneDx RCV000078527 SCV000239064 pathogenic not provided 2017-12-18 criteria provided, single submitter clinical testing The L213P variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database.
Illumina Clinical Services Laboratory,Illumina RCV000150086 SCV000915572 pathogenic Phenylketonuria 2018-08-14 criteria provided, single submitter clinical testing Across a selection of the available literature, the PAH c.638T>C (p.Leu213Pro) missense variant has been reported in seven individuals with phenylalanine hydroxylase (PAH) deficiency, including in six who carried the variant in a compound heterozygous state with a second variant and in one who was heterozygous for the variant with no second identified variant (Guldberg et al. 1996; Tyfield et al. 1997; Bosco et al. 1998; Daniele et al. 2009; Utz et al. 2012; Djordjevic et al. 2012; Polak et al. 2013). Of the compound heterozygotes, five presented with a classic phenylketonuria (PKU) phenotype, while the remaining compound heterozygote and the heterozygote both presented a mild hyperphenylalaninemia phenotype. Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database in a region of good sequence coverage so the variant is presumed to be rare. Based on the collective evidence, the p.Leu213Pro 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000078527 SCV001249186 pathogenic not provided 2019-07-01 criteria provided, single submitter clinical testing
Invitae RCV000150086 SCV001390886 pathogenic Phenylketonuria 2019-09-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 213 of the PAH protein (p.Leu213Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in several individuals affected with phenylketonuria (PKU) (PMID: 8632937, 9521426, 23430547, 22112818, 19292873). ClinVar contains an entry for this variant (Variation ID: 92747). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078527 SCV000119623 not provided not provided no assertion provided not provided

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