Submissions for variant NM_000277.3(PAH):c.441+6T>A

dbSNP: rs199475698

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000106356	SCV001146727	likely pathogenic	Phenylketonuria	2019-08-06	reviewed by expert panel	curation	The c.441+6T>A variant in PAH has been reported in at least 2 patients with PKU (BH4 deficiency ruled out), who carried pathogenic variants (ClinVar IDs: 589 & 576) (PMID: 22526846). This variant is absent from 1000G and ESP, and has an extremely low frequency in gnomAD (MAF= 0.000004). This intronic variant changes a moderately conserved nucleotide, and computational analyses (Alamut) predict that this variant may weaken (~60%) the splice donor site of intron 4. Based on the available information, this variant is considered to be likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP3, PP4_M, PM2, PM3_S.
Invitae	RCV000106356	SCV000958139	pathogenic	Phenylketonuria	2023-10-29	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the PAH gene. It does not directly 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 (rs199475698, gnomAD 0.0009%). This variant has been observed in individual(s) with phenylketonuria (PMID: 22526846, 23357515). ClinVar contains an entry for this variant (Variation ID: 120275). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000106356	SCV001426945	pathogenic	Phenylketonuria	2021-08-19	criteria provided, single submitter	clinical testing	Variant summary: PAH c.441+6T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: one predict the variant abolishes a 5 prime splicing donor site; three predict the variant weakens a 5 prime donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251486 control chromosomes. c.441+6T>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria, e.g. Sterl_2013, Reblova_2013, Hillert_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001563425	SCV001786363	uncertain significance	not provided	2021-03-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32668217, 23357515, 22526846)
Revvity Omics, Revvity	RCV000106356	SCV002020220	likely pathogenic	Phenylketonuria	2022-03-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000106356	SCV004209570	likely pathogenic	Phenylketonuria	2023-09-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001563425	SCV004222246	likely pathogenic	not provided	2023-05-31	criteria provided, single submitter	clinical testing	The PAH c.441+6T>A variant has been reported in the published literature in this variant has been detected in individuals with classic Phenylketonuria (PKU). Those individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 32668217 (2020), 22526846 (2013)). The frequency of this variant in the general population, 0.000004 (1/251486 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper PAH mRNA splicing. Based on the available information, this variant is classified as likely pathogenic.
Inserm U 954, Faculté de Médecine de Nancy	RCV000106356	SCV000143855	probable-pathogenic	Phenylketonuria		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.