ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.490A>G (p.Ile164Val) (rs199475647)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel, RCV000535090 SCV000852171 likely pathogenic Phenylketonuria 2018-08-13 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: ExAC MAF: 0.00012; PP4_Moderate: Detected in patients with PKU/HPA. BH4 deficiency excluded. (PMID:11244681; PMID:23942198); PM3_Strong: Detected with D145V, A403V (Pathogenic) (PMID:11244681; PMID:23942198). 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: (PM2, PP4_Moderate, PM3_Strong).
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088946 SCV000119547 not provided not provided no assertion provided not provided
Invitae RCV000535090 SCV000629194 pathogenic Phenylketonuria 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 164 of the PAH protein (p.Ile164Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs199475647, ExAC 0.01%). This variant has been reported either in combination with another PAH variant (PMID: 23942198, 11244681, Invitae) or with an unknown second allele (PMID: 27121329) in individuals affected with hyperphenylalaninemia. ClinVar contains an entry for this variant (Variation ID: 102698). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). A different missense substitution at this codon (p.Ile164Thr) has been determined to be pathogenic (PMID: 7833954,  17502162, 26666653, 27578510, 9634518). This suggests that the isoleucine 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.

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