Submissions for variant NM_000277.3(PAH):c.912+1G>A

gnomAD frequency: 0.00001  dbSNP: rs62514956

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000150083	SCV000852153	pathogenic	Phenylketonuria	2018-08-10	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency. ExAC MAF=0.00006.; PVS1: Canonical +1 splice site; PP4: Detected in 5 patients with classical PKU. (PMID:8659548). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PVS1, PP4).
Eurofins Ntd Llc (ga)	RCV000078537	SCV000110393	pathogenic	not provided	2017-01-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000078537	SCV000617699	pathogenic	not provided	2020-04-22	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); Not associated with responsiveness to tetrahydrobiopterin (BH4) therapy (Sarkissian et al., 2012); This variant is associated with the following publications: (PMID: 25087612, 29316886, 12649065, 25525159, 24368688, 22841515, 26666653, 17502162, 23430918, 26350204, 29353259, 8659548, 30275481, 32668217)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150083	SCV000696471	pathogenic	Phenylketonuria	2016-01-21	criteria provided, single submitter	clinical testing	Variant summary: This c.912+1G>A variant affects a conserved nucleotide in the canonical splice donor site at intron 8. Thus it is predicted to affect normal splicing (such as exon skipping), resulting in loss of function. Loss-of-function due to mutations in this gene is an established disease mechanism in Phenylketoneuria. 5/5 in silico programs via Alamut predict that this variant abrogates the splice donor site. This variant was found in 4/121156 control chromosomes (including broad and large populations from ExAC) at a frequency of 0.000033, which does not exceed the maximal expected frequency of a pathogenic allele (0.0079057) in this gene. This variant has been reported in several PKU patients, including patients with concordant recessive genotypes. One clinical lab and reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000150083	SCV000939654	pathogenic	Phenylketonuria	2024-08-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 of the PAH gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62514956, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with phenylketonuria (PMID: 17502162, 26666653). ClinVar contains an entry for this variant (Variation ID: 92752). 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.
Baylor Genetics	RCV000150083	SCV001163716	pathogenic	Phenylketonuria	2024-02-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000150083	SCV002060199	pathogenic	Phenylketonuria	2021-11-10	criteria provided, single submitter	clinical testing	NM_000277.1(PAH):c.912+1G>A is a canonical splice variant classified as pathogenic in the context of phenylalanine hydroxylase deficiency. c.912+1G>A has been observed in cases with relevant disease (PMID: 11385716, 10598814, 28982351). Functional assessments of this variant are not available in the literature. c.912+1G>A has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_000277.1(PAH):c.912+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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000078537	SCV000119767	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000150083	SCV001463133	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing