Submissions for variant NM_000277.3(PAH):c.842+1G>A

gnomAD frequency: 0.00004  dbSNP: rs5030852

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000000630	SCV000852168	pathogenic	Phenylketonuria	2018-08-13	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PVS1: Canonical +1 splice site; PM2: gnomAD MAF 0.00008; PP4: Reported in 3 PKU populations: Slovak, Germany, Italy (PMID:1671810; PMID:10394930; PMID:23764561); PM3: (PMID:20188615; PMID:24941924). 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: (PVS1, PM2, PP4, PM3).
Counsyl	RCV000000630	SCV000221050	likely pathogenic	Phenylketonuria	2015-01-16	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000630	SCV000629220	pathogenic	Phenylketonuria	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 7 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 (rs5030852, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with phenylketonuria (PMID: 16256386, 20188615, 23764561, 24941924). This variant is also known as IVS VII-1G>A and IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 599). 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000000630	SCV000803785	likely pathogenic	Phenylketonuria	2017-08-16	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000089129	SCV001249177	pathogenic	not provided	2019-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000000630	SCV001361327	pathogenic	Phenylketonuria	2020-12-14	criteria provided, single submitter	clinical testing	Variant summary: PAH c.842+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.4e-05 in 251272 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (4.4e-05 vs 0.0079), allowing no conclusion about variant significance. c.842+1G>A has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria; Example: Dianzani_1991, Leuzzi_2006, Aldamiz-Echevarria_2016, Li_2018). 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. Six other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen PAH Variant Curation Expert Panel) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Elsea Laboratory, Baylor College of Medicine	RCV000000630	SCV001424295	pathogenic	Phenylketonuria	2020-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000089129	SCV001820031	pathogenic	not provided	2021-01-05	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: 32668217, 31589614, 30747360, 26666653, 25525159, 23764561, 20188615, 16256386, 24941924, 26589311, 20920871, 1671810, 17935162)
Revvity Omics, Revvity	RCV000000630	SCV002016504	pathogenic	Phenylketonuria	2023-09-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000000630	SCV004201341	pathogenic	Phenylketonuria	2024-02-21	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000000630	SCV004848855	pathogenic	Phenylketonuria	2022-11-03	criteria provided, single submitter	clinical testing	The c.842+1G>A in PAH has been reported in at least 6 homozygous and over 50 compound heterozygous individuals affected with Hyperphenylalaninemia or Phenylketonuria (selected publications: Hillert 2020 PMID: 32668217). This variant was classified as Pathogenic on August 13, 2018 by the ClinGen-approved ClinGen PAH Variant Curation Expert Panel (Variation ID 599) and was identified in 5/68040 European and in 1/10608 Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. Loss of function of the PAH gene is an established disease mechanism in autosomal recessive Phenylketonuria. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperphenylalanemia/phenylkenonuria. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PM3_Very Strong.
Neuberg Centre For Genomic Medicine, NCGM	RCV000000630	SCV005400814	pathogenic	Phenylketonuria	2023-06-22	criteria provided, single submitter	clinical testing	The observed splice donor variant c.842+1G>A in the PAH gene has been reported previously in multiple individuals with phenylketonuria (Vieira Neto E, et al., 2018; Vela-Amieva M, et al., 2015). This variant is reported with the allele frequency 0.004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic by multiple submitters with a status of reviewed by expert panel. The variant affects the GT donor splice site downstream of exon 7. Loss of function variants have been previously reported to be disease causing. The variant is predicted to be damaging by SpliceAI prediction tool. For these reasons, this variant has been classified as Pathogenic.
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV004798708	SCV005420352	pathogenic	Hyperphenylalaninemia	2024-10-04	criteria provided, single submitter	research	PVS1, PM2, PP4, PM3
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089129	SCV005624698	pathogenic	not provided	2024-10-30	criteria provided, single submitter	clinical testing	The PAH c.842+1G>A variant disrupts a canonical splice-donor site and interferes with normal PAH mRNA splicing. This variant has been reported in the published literature in individuals with phenylketonuria (PKU) phenotypes, including mild PKU, classic PKU, and hyperphenylalaninemia (HPA) (PMIDs: 38105685 (2023), 36845377 (2023), 34828281 (2021), 33465300 (2021), 33375644 (2020), 30747360 (2019), 30050108 (2018), 27121329 (2016), 24941924 (2015), 23932990 (2013), 23856132 (2013), 23764561 (2013), 23430918 (2012), 20920871 (2011), 20188615 (2010), 19609714 (2009), 19444284 (2009), 17096675 (2007), 16601866 (2006), 16256386 (2005), 16198137 (2005), 12655553 (2003), 12649065 (2003), 10394930 (1999), 1671810 (1991)). The frequency of this variant in the general population, 0.000078 (10/128996 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000000630	SCV000020780	pathogenic	Phenylketonuria	1991-03-01	no assertion criteria provided	literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089129	SCV000119739	not provided	not provided		no assertion provided	not provided
Natera, Inc.	RCV000000630	SCV001453098	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000089129	SCV001929136	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000089129	SCV001960095	likely pathogenic	not provided		no assertion criteria provided	clinical testing