ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.842+4A>G

dbSNP: rs1555204434
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000721176 SCV000852104 likely pathogenic Phenylketonuria 2018-08-12 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PP3: HSF: Broken WT Donor Site, New Donor Site. MaxEnt: Broken WT Donor Site.; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4_Moderate: IVS7+4A>G seen in 2 PKU patients. BH4 deficiency was ruled out. Upgraded per ClinGen PAH EP. (PMID:21147011); PM3: Detected in trans with A300S, pathogenic in ClinVar (PMID:21147011). 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: (PP3, PM2, PP4_Moderate, PM3).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506590 SCV000601719 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000721176 SCV003441007 pathogenic Phenylketonuria 2024-01-26 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 not present in population databases (gnomAD no frequency). This variant has been observed in individuals with hyperphenylalaninemia (PMID: 21147011, 32668217). This variant is also known as IVS7+4A>G. ClinVar contains an entry for this variant (Variation ID: 439228). 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.
GeneDx RCV004719845 SCV005326098 likely pathogenic not provided 2023-08-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25525159, 21147011, 35281663, 32668217)

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