ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs62507324
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
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
Invitae RCV000409987 SCV000629221 pathogenic Phenylketonuria 2024-01-01 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 2023-03-12 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.