ClinVar Miner

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

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Total submissions: 4
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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).
Counsyl RCV000178066 SCV000800700 uncertain significance Phenylketonuria 2018-04-25 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790751 SCV000230056 likely pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing
Invitae RCV000178066 SCV000827282 uncertain significance Phenylketonuria 2018-04-12 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 an individual affected with mild  hyperphenylalaninemia (PMID: 21147011). 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.

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