ClinVar Miner

Submissions for variant NM_000277.2(PAH):c.441+4A>G (rs62508586)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669322 SCV000794065 uncertain significance Phenylketonuria 2017-09-07 criteria provided, single submitter clinical testing
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088922 SCV000119520 not provided not provided no assertion provided not provided
Invitae RCV000669322 SCV000814138 likely pathogenic Phenylketonuria 2018-06-21 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the PAH gene. It does not directly change the encoded amino acid sequence of the PAH protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with a pathogenic PAH variant in an individual affected with phenylketonuria (Invitae) and in heterozygosis (no second variant described) in an individual affected with PAH-related disease (PMID: 28676969). ClinVar contains an entry for this variant (Variation ID: 102674). Nucleotide substitutions within 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, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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