ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs62516060
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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 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

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