Submissions for variant NM_000277.3(PAH):c.1150C>T (p.Pro384Ser)

dbSNP: rs1555203677

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000666283	SCV002032225	uncertain significance	Phenylketonuria	2021-04-23	reviewed by expert panel	curation	The c.1150C>T (p.Pro384Ser) PAH variant has been reported in at least one “phenylketonuria” or “hyperphenylalaninemia” proband (PMID: 31332730). This variant is absent from 1000G, ESP, and gnomAD databases. It is a missense variant predicted deleterious by Polyphen (probably damaging), MutationTaster (disease causing), and has a REVEL score of 0.902. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP3.
Counsyl	RCV000666283	SCV000790548	uncertain significance	Phenylketonuria	2017-03-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779045	SCV002015060	uncertain significance	not specified	2021-10-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1150C>T (p.Pro384Ser) results in a non-conservative amino acid change located in the Aromatic amino acid hydroxylase, C-terminal domain (IPR019774) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251242 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1150C>T in individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) has been reported although it has been cited as being a mild variant in the literature (example, Shen_2016, Trunzo_2016, Zhang_2016) and has also been subsequently cited by others without primary evidence supporting pathogenicity (example, Kuznetcova_2019, Hillert_2020). Multiple overlapping publications report experimental evidence evaluating an impact on protein function (example, Shen_2016, Trunzo_2016, Zhang_2016). The most pronounced variant effect results in >50%-90% of normal phenylalanine hydroxylase enzyme activity in-vitro and positive interallelic complementation when analyzed as a compound heterozygous genotype with p.R408W. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing an overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000666283	SCV003441214	uncertain significance	Phenylketonuria	2022-06-15	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 384 of the PAH protein (p.Pro384Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with PAH-related conditions (PMID: 26803807, 32668217). ClinVar contains an entry for this variant (Variation ID: 551270). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PAH function (PMID: 26803807). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.