ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.520A>G (p.Ile174Val) (rs199475632)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000675155 SCV000852115 likely pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Not found in any population databases; PP3: All predictors agree--damaging; PM3: Single patient IVS4+5G>T (null) / I174V (Bercovich 2008 PMID 18299955) (PMID:18299955); PP4: Two independent patients (one in Zschocke (PMID 10394930) and one in Bercovich (PMID 18299955) with "PKU". While no specific levels are mentioned, they are followed in clinic and were diagnosed with Phe >120umol/L. BH4 defect WAS NOT excluded in either paper.. 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, PP3, PM3, PP4).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000088968 SCV000203187 uncertain significance not provided 2015-09-29 criteria provided, single submitter clinical testing
Invitae RCV000675155 SCV001220737 pathogenic Phenylketonuria 2019-01-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 174 of the PAH protein (p.Ile174Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another PAH variant in individuals affected with PAH-related disease (PMID: 27121329, 18299955, 22526846). ClinVar contains an entry for this variant (Variation ID: 102720). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). This variant disrupts the p.Ile174 amino acid residue in PAH. Other variant(s) that disrupt this residue have been observed in individuals with PAH-related conditions (PMID: 23842451), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000675155 SCV001361067 pathogenic Phenylketonuria 2019-08-05 criteria provided, single submitter clinical testing Variant summary: PAH c.520A>G (p.Ile174Val) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251110 control chromosomes. c.520A>G has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (mild-PKU/Non-PKU-HPA, Phenylketonuria)(Zschocke_1999, Bercovich_2008, Couce_2013, Yang_2001, Sterl_2013, Reblova_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories (n=1, Likely pathogenic; n=1, VOUS) and one expert panel (Likely pathogenic, ClinGen) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000088968 SCV001370959 pathogenic not provided 2020-04-01 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088968 SCV000119571 not provided not provided no assertion provided not provided
Counsyl RCV000675155 SCV000800768 likely pathogenic Phenylketonuria 2017-06-02 no assertion criteria provided clinical testing

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