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

gnomAD frequency: 0.00001  dbSNP: rs199475647

Total submissions: 7

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).
Invitae	RCV000535090	SCV000629194	pathogenic	Phenylketonuria	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 164 of the PAH protein (p.Ile164Val). This variant is present in population databases (rs199475647, gnomAD 0.006%). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 11244681, 23942198, 27121329; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102698). 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 not expected to disrupt PAH protein function with a negative predictive value of 80%. This variant disrupts the p.Ile164 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7833954, 9634518, 17502162, 26666653, 27578510). 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV002251981	SCV002522964	likely pathogenic	See cases	2021-12-30	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2, PM3, PP4
Fulgent Genetics, Fulgent Genetics	RCV000535090	SCV002812610	pathogenic	Phenylketonuria	2021-10-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114254	SCV003800709	pathogenic	6-Pyruvoyl-tetrahydrobiopterin synthase deficiency	2023-01-27	criteria provided, single submitter	clinical testing	Variant summary: PAH c.490A>G (p.Ile164Val) results in a conservative amino acid change located in the aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251370 control chromosomes (gnomAD). c.490A>G has been reported in the literature in the compound heterozygous state in multiple individuals affected with hyperphenylalaninemia/phenylketonuria (e.g. Mallolas_1999, Trujillano_2014, Wang_2018, Ferreira_2021) . 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. Four submitters, including the ClinGen PAH Variant Curation Expert Panel, have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as either pathogenic (n=2) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000535090	SCV004209614	pathogenic	Phenylketonuria	2023-08-22	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088946	SCV000119547	not provided	not provided		no assertion provided	not provided