ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1315+4A>G (rs62508649)

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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 RCV000672561 SCV001250567 likely pathogenic Phenylketonuria 2019-11-05 reviewed by expert panel curation This c.1315+4A>G variant was documented twice in patients from Southern China and once in a patient from Northern China with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in trans with a pathogenic or likely pathogenic PAH variant in four patients diagnosed with PAH deficiency (PMID: 16256386, 28982351, 25456745, 23932990). This variant is present in the population database gnomAD at a frequency below 0.0002. According to in silico splicing predictions, this alteration is probably damaging (TraP score 0.992). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3.
Counsyl RCV000672561 SCV000797674 likely pathogenic Phenylketonuria 2018-02-08 criteria provided, single submitter clinical testing
Invitae RCV000672561 SCV000961175 pathogenic Phenylketonuria 2018-12-13 criteria provided, single submitter clinical testing This sequence change falls in intron 12 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 multiple individuals affected with phenylalanine hydroxylase deficiency (PMID: 16256386, 23932990). This variant is also known as IVS12+4A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 102589). 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. For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088828 SCV000119420 not provided not provided no assertion provided not provided

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