Submissions for variant NM_000277.3(PAH):c.970A>G (p.Ile324Val)

gnomAD frequency: 0.00001  dbSNP: rs1221031352

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001269315	SCV001448666	uncertain significance	Phenylketonuria	2020-07-25	reviewed by expert panel	curation	The NM_000277.3:c.970A>G (p.Ile324Val) variant is a missense variant in exon 10/13 of PAH. It has been previously reported in a patient with mild hyperphenylalanemia (plasma Phe 230 uM) in confirmed trans with the c.441+5G>T variant (ClinVar Pathogenic (ID 92742); Pathogenic per ClinGen PAH VCEP); BH4 deficiency was not stated to have been excluded (PP4; PM3) (PMID: 15159646). The variant is absent from ethnically diverse control databases, including gnomAD/ExAC, 1000 Genomes, and ESP (PM2). In-silico pathogenicity predictors are conflicting and REVEL=0.534, such that PP3 is not met. Classification: VUS – insufficient evidence Supporting Criteria: PM2; PM3; PP4
Labcorp Genetics (formerly Invitae), Labcorp	RCV001269315	SCV003513852	pathogenic	Phenylketonuria	2024-03-07	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 324 of the PAH protein (p.Ile324Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hyperphenylalaninemia (PMID: 15159646). 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: 987909). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant disrupts the p.Ile324 amino acid residue in PAH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15159646, 24327145, 29731766). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004690041	SCV005184382	uncertain significance	not specified	2024-05-01	criteria provided, single submitter	clinical testing	Variant summary: PAH c.970A>G (p.Ile324Val) results in a conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal (IPR019774) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250620 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.970A>G has been reported in the literature in an individual mildly affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Johnston_2004). This report does not provide unequivocal conclusions about association of the variant with Phenylalanine Hydroxylase Deficiency (Phenylketonuria). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 15159646). ClinVar contains an entry for this variant (Variation ID: 987909). Based on the evidence outlined above, the variant was classified as uncertain significance.