ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.500A>T (p.Asn167Ile) (rs77554925)

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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 RCV000412232 SCV000852095 likely pathogenic Phenylketonuria 2018-08-28 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in ExAC (MAF=0.00003). Absent from gnomAD, 1000G, ESP; PP4_Moderate: Found in a French patient with HPA and 2 unrelated UK patients. BH4 deficiencies not assessed/reported. Seen in 1 German patient, Cofactor deficiency was excluded by the BH4 test. 1 Spanish patient, a defect in the synthesis or regeneration pathways of 6R-BH4 was ruled out by analyzing urinary pterin levels and measuring dihydropteridine reductase activity. (PMID:26666653; PMID:9012412; PMID:10679941); PM3_Strong: Patient 664 with genotype N167I/Rl58Q (Pathogenic in ClinVar). Detected with G272X and R408W, known pathogenic variants. (PMID:24368688; PMID:26666653). 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).
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078523 SCV000110379 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing
Counsyl RCV000412232 SCV000485290 likely pathogenic Phenylketonuria 2015-12-29 criteria provided, single submitter clinical testing
Invitae RCV000412232 SCV000830097 pathogenic Phenylketonuria 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 167 of the PAH protein (p.Asn167Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs77554925, ExAC 0.003%). This variant has been reported in combination with another PAH variant in several individuals affected with PKU or HPA (PMID: 9452062, 10234516, 26666653, 24368688, 23430918, 22112818, Invitae), being reported on the opposite chromosome (in trans) from other pathogenic variant in an individual affected with carnitine deficiency (Invitae). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 92743). Experimental studies have shown that this missense change does not have an effect on the enzyme catalytic kinetics; however, authors pointed out that this variant causes the protein to aggregate so its effect may be in misfolding (PMID: 12554741). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000412232 SCV001623309 pathogenic Phenylketonuria 2021-04-20 criteria provided, single submitter clinical testing Variant summary: PAH c.500A>T (p.Asn167Ile) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, 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 3.6e-05 in 251360 control chromosomes. c.500A>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; e.g. Tyfield_1997, Desviat_1999, Utz_2011, Jeannesson-Thivisol_2015). These data indicate that the variant is very likely to be associated with disease. A functional study investigating the variant effects in E. coli reported that the variant did not appear to significantly alter the kinetic properties of the enzyme, but suggested that it may de-stabilize the secondary structure of the protein, resulting in aggregation (e.g. Carvalho_2003). Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as uncertain significance (n=1) and pathogenic/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000078523 SCV000119553 not provided not provided no assertion provided not provided

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