ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.289A>C (p.Ile97Leu) (rs142516271)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000430873 SCV000510911 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Converted during submission to Uncertain significance.
ClinGen PAH Variant Curation Expert Panel, RCV000664524 SCV000852114 uncertain significance Phenylketonuria 2018-08-07 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: BP4: Tolerated in SIFT, benign in Polyphen-2, Polymorphism in MutationTaster. REVEL=0.511; PP4: Seen in patient with mild HPA (PMID:17627389). In summary this variant meets criteria to be classified as uncertain significance for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (BP4, PP4).
Counsyl RCV000664524 SCV000788501 uncertain significance Phenylketonuria 2017-01-25 criteria provided, single submitter clinical testing
Invitae RCV000664524 SCV000832765 uncertain significance Phenylketonuria 2018-06-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 97 of the PAH protein (p.Ile97Leu). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs142516271, ExAC 0.2%). This variant has been observed as a single heterozygous change in an individual affected with mild hyperphenylalaninemia (PMID: 17627389). ClinVar contains an entry for this variant (Variation ID: 376937). 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 tolerated, 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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