Submissions for variant NM_000277.3(PAH):c.1198A>C (p.Arg400=)

dbSNP: rs199475593

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000088787	SCV000331126	uncertain significance	not provided	2015-09-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000671619	SCV000796609	uncertain significance	Phenylketonuria	2017-12-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479000	SCV004223263	uncertain significance	not specified	2023-11-30	criteria provided, single submitter	clinical testing	Variant summary: PAH c.1198A>C (p.Arg400Arg) alters a conserved nucleotide located close to a canonical splice site (the penultimate nucleotide of exon 11) and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 allele was found at a frequency of 4e-06 in 251292 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1198A>C has been reported in the literature in at least two individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) or hyperphenylalaninemia (e.g., Eisensmith_1996, Narravula_2017, Hillert_2020, Vela-Amieva_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8632937, 27308838, 32668217, 34828281). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000671619	SCV004294259	pathogenic	Phenylketonuria	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change affects codon 400 of the PAH mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PAH protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs199475593, gnomAD 0.007%). This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 8632937, 34828281; Invitae). ClinVar contains an entry for this variant (Variation ID: 102553). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088787	SCV000119374	not provided	not provided		no assertion provided	not provided