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

gnomAD frequency: 0.00001  dbSNP: rs62508693

Total submissions: 4

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000758133	SCV002190576	pathogenic	Phenylketonuria	2021-10-10	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. 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. 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