ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.355C>T (p.Pro119Ser) (rs398123292)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000178066 SCV000852139 likely pathogenic Phenylketonuria 2018-07-29 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PP3: in silico analysis supportive of damaging effect; PM3_Strong: In trans with R261Q (PMID 21147011), and in trans with IVS2+1G>A (PMID 12655554) (PMID:21147011; PMID:12655554); PP4_Moderate: BH4 deficiency excluded (PMID:21147011). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PP3, PM3_Strong, PP4_Moderate).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790751 SCV000230056 likely pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing
Counsyl RCV000178066 SCV000800700 uncertain significance Phenylketonuria 2018-04-25 criteria provided, single submitter clinical testing
Invitae RCV000178066 SCV000827282 uncertain significance Phenylketonuria 2019-12-24 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 119 of the PAH protein (p.Pro119Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs398123292, ExAC 0.3%). This variant has been reported in combination with another PAH variant in individuals affected with mild hyperphenylalaninemia (PMID: 21147011, 12655554). ClinVar contains an entry for this variant (Variation ID: 92741). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics RCV000178066 SCV001163726 likely pathogenic Phenylketonuria criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000178066 SCV001362288 likely pathogenic Phenylketonuria 2019-02-22 criteria provided, single submitter clinical testing Variant summary: PAH c.355C>T (p.Pro119Ser) results in a non-conservative amino acid change located in the 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 0.00029 in 246122 control chromosomes, predominantly at a frequency of 0.0022 within the South Asian subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (0.0022 vs. 0.0079), allowing no conclusion about variant significance. c.355C>T has been reported in the literature in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Dobrowolski_2011, Esfahani_2018, Lindner_2003). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories/databases (evaluation after 2014) cite the variant with conflicting classification, twice as likely pathogenic, and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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