Submissions for variant NM_000277.3(PAH):c.982A>G (p.Thr328Ala)

gnomAD frequency: 0.00001  dbSNP: rs199475616

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV001854516	SCV002540161	likely pathogenic	Phenylketonuria	2020-09-25	reviewed by expert panel	curation	The c.982A>G (p.Thr328Ala) variant in PAH has been reported in 1 individual with PKU (BH4 deficiency excluded), detected with pathogenic variant p.L48S (PMID: 21147011). This variant has extremely low frequency in ExAC and gnomAD (MAF=0.00003). Computational evidence supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3_supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854516	SCV002247386	pathogenic	Phenylketonuria	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 328 of the PAH protein (p.Thr328Ala). This variant is present in population databases (rs199475616, gnomAD 0.003%). This missense change has been observed in individual(s) with hyperphenylalaninemia and/or phenylketonuria (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: 102923). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001854516	SCV002819787	likely pathogenic	Phenylketonuria	2022-12-24	criteria provided, single submitter	clinical testing	Variant summary: PAH c.982A>G (p.Thr328Ala) 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 allele was found at a frequency of 1.2e-05 in 250852 control chromosomes (gnomAD). c.982A>G has been reported in the literature in at least one compound heterozygous individual affected with Classical Phenylalanine Hydroxylase Deficiency (Phenylketonuria, Dobrowolski_2011). The variant was also found occuring in cis in one individual with mild Phenylketonuria (Ozturk_2022). These data do not allow any conclusion about variant significance. Relative residual activity from the sum of p.Leu48Ser and p.Thr328Ala resulted in a PAH activity of 19.5% (Dobrowolski_2011). Two ClinVar submitters, including one expert panel (ClinGen PAH Variant Curation Expert Panel), have assessed the variant since 2014: one classified the variant as likely pathogenic (expert panel) and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV000089190	SCV005326097	likely pathogenic	not provided	2023-08-12	criteria provided, single submitter	clinical testing	Different missense changes at this residue (T328P, T328N) have been reported in the published literature (Kuznetcova et al., 2019; Li et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21147011, 35405047, 31332730, 26503515)
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089190	SCV000119806	not provided	not provided		no assertion provided	not provided