ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.848T>A (p.Ile283Asn)

gnomAD frequency: 0.00001  dbSNP: rs62508693
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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 RCV000758133 SCV000886619 pathogenic Phenylketonuria 2018-12-09 reviewed by expert panel curation The c.848T>A (p.Ile283Asn) variant in PAH is absent from population databases and predicted damaging with in silico predictors. It is a novel missense change in a residue where a different pathogenic variant has been identified (c.847A>T (p.Ile283Phe). It has been identified in multiple affected individuals in trans with known pathogenic variants (PMID: 9521426, 26413448), and was identified in a patient in which a defect in BH4 metabolism had been excluded. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PM5, PP4_Moderate, PP3.
Invitae RCV000758133 SCV002190576 pathogenic Phenylketonuria 2021-10-10 criteria provided, single submitter clinical testing Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAH protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ile283 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8097423, 11161839, 24350308, 25596310). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 102877). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 9521426, 32668217). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with asparagine at codon 283 of the PAH protein (p.Ile283Asn). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and asparagine.
Baylor Genetics RCV000758133 SCV004209682 pathogenic Phenylketonuria 2023-04-13 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089138 SCV000119749 not provided not provided no assertion provided not provided

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