Submissions for variant NM_000277.3(PAH):c.60+5G>T

gnomAD frequency: 0.00003  dbSNP: rs62514895

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000089000	SCV000224180	pathogenic	not provided	2014-11-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000089000	SCV000239043	pathogenic	not provided	2020-01-08	criteria provided, single submitter	clinical testing	Reduces the quality of the splice donor site in intron 1, and is expected to cause abnormal gene splicing (Vela-Amieva et al., 2015); This variant is associated with the following publications: (PMID: 25596310, 24368688, 23514811, 23430918, 24941924, 25525159, 8406445, 27121329, 18937047, 17935162, 17443661, 15171997, 23792259, 22841515, 22112818, 20188615, 11180595, 10598814, 9399896, 31589614, 32668217)
Invitae	RCV000173096	SCV000629202	pathogenic	Phenylketonuria	2024-01-20	criteria provided, single submitter	clinical testing	This sequence change falls in intron 1 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 (rs62514895, gnomAD 0.02%). This variant has been observed in individuals with phenylketonuria or hyperphenylalaninemia (PMID: 24368688, 24941924; Invitae). ClinVar contains an entry for this variant (Variation ID: 102751). 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.
Ambry Genetics	RCV000624585	SCV000741698	pathogenic	Inborn genetic diseases	2014-09-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089000	SCV000888351	pathogenic	not provided	2018-03-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000173096	SCV001361330	pathogenic	Phenylketonuria	2019-12-13	criteria provided, single submitter	clinical testing	Variant summary: PAH c.60+5G>T alters a non-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: Five predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 7.2e-05 in 251412 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PAH causing Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (7.2e-05 vs 0.0079), allowing no conclusion about variant significance. c.60+5G>T has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) (Sarkissian_2011, Bueno_2013). These data indicate that the variant is very likely to be associated with disease. PAH activity in vitro was null according to PAHdb (http://www.pahdb.mcgill.ca) via Bueno_2013. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000089000	SCV001747665	pathogenic	not provided	2021-10-01	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000173096	SCV002016468	pathogenic	Phenylketonuria	2022-08-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003415875	SCV004112873	pathogenic	PAH-related condition	2022-09-08	criteria provided, single submitter	clinical testing	The PAH c.60+5G>T variant is predicted to interfere with splicing. This sequence variant, which lies near the junction of exon 1 and intron 1, has been reported as causative for phenylalanine hydroxylase deficiency (e.g., Guldberg et al. 1993. PubMed ID: 8406445, referred to as IVS-1nt5(g-->t); Vela-Amieva et al. 2015. PubMed ID: 24941924). Available splicing prediction programs predict that this variant would weaken the canonical splice donor site at this location (Alamut Visual v2.11), although to our knowledge this prediction has not been confirmed with functional studies. In the BioPKU database, the c.60+5G>T variant has been reported to have a severe phenotypic effect and is listed as a variant associated with classic phenylketonuria (PKU) (see the PAHvdb page at www.biopku.org). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-103310844-C-A), which is consistent with it being reported as a founder variant in the Mexican population (Vela-Amieva et al. 2021. PubMed ID: 34828281). Multiple independent submitters to ClinVar interpret this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/102751). Based on the collective evidence, this variant is interpreted as pathogenic.
Baylor Genetics	RCV000173096	SCV004209580	pathogenic	Phenylketonuria	2023-09-19	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089000	SCV000119604	not provided	not provided		no assertion provided	not provided
Counsyl	RCV000173096	SCV000790051	pathogenic	Phenylketonuria	2017-03-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000173096	SCV001459231	pathogenic	Phenylketonuria	2020-09-16	no assertion criteria provided	clinical testing