Submissions for variant NM_000277.3(PAH):c.997C>T (p.Leu333Phe)

gnomAD frequency: 0.00001  dbSNP: rs62516060

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV002259565	SCV002540156	pathogenic	Phenylketonuria	2022-03-13	reviewed by expert panel	curation	The c.997C>T (p.Leu333Phe) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). It was detected with multiple pathogenic variants: p.E390G (PMID: 8098245); p.R261Q (PMID: 21147011); p.S110L (LP by PAH VCEP, PMID: 26542770). This variant is absent in population databases. In an eukaryotic expression system, the L333F mutant had 7% PAH activity as compared to wild type (PMID: 10479481). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as Pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PP4_Moderate, PM2, PP3, PS3_supporting.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002259565	SCV003928911	pathogenic	Phenylketonuria	2023-04-27	criteria provided, single submitter	clinical testing	Variant summary: PAH c.997C>T (p.Leu333Phe) 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 was absent in 251062 control chromosomes. c.997C>T has been reported in the literature as a biallelic genotype in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (example, Abadie_1993, Benit_1999, Zare-Karizi_2011, Bayat_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 7% of normal PAH enzyme activity in vitro (Benit_1999). The following publications have been ascertained in the context of this evaluation (PMID: 8098245, 26542770, 10479481, 20920871). One expert panel (ClinGen PAH Variant Curation Expert Panel) has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Cellular and Molecular Medicine Research Institute, Urmia University of Medical Sciences	RCV002259565	SCV004035239	pathogenic	Phenylketonuria	2023-09-19	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002259565	SCV005053820	pathogenic	Phenylketonuria	2024-03-02	criteria provided, single submitter	clinical testing
OMIM	RCV000000655	SCV000020805	pathogenic	Hyperphenylalaninemia	1993-01-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089195	SCV000119811	not provided	not provided		no assertion provided	not provided