Submissions for variant NM_000277.3(PAH):c.441+1G>A

gnomAD frequency: 0.00001  dbSNP: rs62517166

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000169579	SCV001572866	pathogenic	Phenylketonuria	2018-12-22	reviewed by expert panel	curation	The c.441+1G>A variant in PAH is a canonical splice variant in +1 splice site (exon 3/4 junction) in the canonical transcript of PAH, a gene fulfilling the most recent criteria for LOF being a known disease mechanism (PVS1; see PVS1: Recommendations for Interpreting the Loss of Function PVS1 ACMG/AMP Variant Criteria). In addition, the variant has been previously shown by RT-PCR analysis to alter RNA splicing (PS3_Supporting; PMID: 8535445). It is ultra-rare (highest observed population frequency 0.00001, with zero homozygotes, in gnomAD Non-Finnish European subpopulation), well under the PAH-specific frequency cutoff of 0.0002 (PM2). It has been found in multiple probands with classic PKU (e.g., PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308, 23430918, 23764561, 8535445), although BH4 deficiency does not appear to have been formally excluded (PP4), including in trans with the Clinvar-Pathogenic R408W allele (PMID: 22112818) (PM3).
Eurofins Ntd Llc (ga)	RCV000088919	SCV000230055	pathogenic	not provided	2014-11-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169579	SCV000696448	pathogenic	Phenylketonuria	2016-07-18	criteria provided, single submitter	clinical testing	Variant summary: The PAH c.441+1G>A variant is located at a conserved intronic position, known to affect splicing, with 5/5 splice prediction tools predicting a significant effect on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 1/121412, which does not exceed the estimated maximal expected allele frequency for a pathogenic PAH variant of 1/126. Multiple publications cite the variant in affected individuals, along with multiple reputable databases/clinical laboratories classify the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae	RCV000169579	SCV000754085	pathogenic	Phenylketonuria	2023-09-08	criteria provided, single submitter	clinical testing	This variant is present in population databases (rs62517166, gnomAD 0.0009%). This sequence change affects a donor splice site in intron 4 of the PAH gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Disruption of this splice site has been observed in individual(s) with PAH-related conditions (PMID: 7726156, 8535445, 16256386, 17096675, 20187763, 22112818, 24350308). This variant is also known as IVS4+1G>A. ClinVar contains an entry for this variant (Variation ID: 102671). Studies have shown that disruption of this splice site results in skipping of exon 4 and introduces a premature termination codon (PMID: 8535445). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000088919	SCV001812888	pathogenic	not provided	2020-02-02	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26600521, 16256386, 22112818, 23357515, 22841515, 17096675, 23430918, 8535445, 25087612)
Myriad Genetics, Inc.	RCV000169579	SCV002060212	pathogenic	Phenylketonuria	2021-11-08	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.441+1G>A is a canonical splice variant classified as pathogenic in the context of phenylalanine hydroxylase deficiency. Please note c.441+1G>A is associated with classic PKU. c.441+1G>A has been observed in cases with relevant disease (PMID: 32668217). Functional assessments of this variant are not available in the literature. c.441+1G>A has been observed in population frequency databases (gnomAD: NFE 0.001%). In summary, NM_000277.1(PAH):c.441+1G>A is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics	RCV000169579	SCV002797098	pathogenic	Phenylketonuria	2022-02-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515782	SCV003720476	pathogenic	Inborn genetic diseases	2022-01-12	criteria provided, single submitter	clinical testing	The c.441+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 4 of the PAH gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (1/251482) total alleles studied. The highest observed frequency was <0.01% (1/113762) of European (non-Finnish) alleles. The c.441+1G>A alteration (also described as IVS4+1G>A in the literature) has been reported in multiple patients with phenylalanine hydroxylase deficiency in the compound heterozygous state with various second alterations (Ramus, 1995; Song, 2005; Bonyadi, 2010; Quirk, 2012; Utz, 2012). In addition, several other alterations affecting the same splice site have also been described in affected patients (Hillert, 2020). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.
Revvity Omics, Revvity	RCV000169579	SCV003822282	pathogenic	Phenylketonuria	2022-04-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169579	SCV004209693	pathogenic	Phenylketonuria	2023-03-21	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000088919	SCV000119517	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000169579	SCV001455108	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing