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

gnomAD frequency: 0.00001  dbSNP: rs62507324

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen PAH Variant Curation Expert Panel	RCV000409987	SCV000852122	likely pathogenic	Phenylketonuria	2018-09-11	reviewed by expert panel	curation	PAH-specific ACMG/AMP criteria applied: PM2: Extremely low frequency in gnomAD+ExAC (MAF=0.00006). Absent from 1000G, ESP.; PP4_Moderate: Detected in Costa Rican and 1 Spanish PKU patients, exclusion of defects in tetrahydrobiopterine metabolism. (PMID:8860005; PMID:8981952); PM3_Strong: Detected in trans with I269L and R408W, known pathogenic variants. (PMID:9521426; PMID:23430918). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP4_Moderate, PM3_Strong).
Eurofins Ntd Llc (ga)	RCV000089132	SCV000341659	pathogenic	not provided	2018-07-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000409987	SCV000485984	pathogenic	Phenylketonuria	2016-03-14	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000409987	SCV000629221	pathogenic	Phenylketonuria	2024-07-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 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 (rs62507324, gnomAD 0.006%). This variant has been observed in individual(s) with phenylketonuria or mild hyperphenylalaninemia (PMID: 8860005, 8981952, 17096675, 19292873, 23430918, 23792259, 23942198, 24368688). This variant is also known as IVS7+3G>C. ClinVar contains an entry for this variant (Variation ID: 102871). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000089132	SCV001470038	pathogenic	not provided	2019-09-09	criteria provided, single submitter	clinical testing	The best available variant frequency is uninformative. Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls.
New York Genome Center	RCV000409987	SCV001622879	likely pathogenic	Phenylketonuria	2020-06-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000409987	SCV002511465	pathogenic	Phenylketonuria	2022-04-25	criteria provided, single submitter	clinical testing	Variant summary: PAH c.842+3G>C 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: Three predict the variant abolishes a 5' splicing donor site. One predict the variant weakens a 5' donor site. The variant allele was found at a frequency of 1.2e-05 in 251272 control chromosomes. c.842+3G>C has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria) in the homozygous and compound heterozygous state (eg. Santos_1996, Jeannesson-Thivisol_2015, Aldamiz-Echevarria_2016, etc). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000409987	SCV002813875	pathogenic	Phenylketonuria	2022-01-11	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000409987	SCV004209694	likely pathogenic	Phenylketonuria	2023-12-19	criteria provided, single submitter	clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE	RCV000089132	SCV000119742	not provided	not provided		no assertion provided	not provided