ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.842+3G>C (rs62507324)

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Total submissions: 5
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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).
Counsyl RCV000409987 SCV000485984 pathogenic Phenylketonuria 2016-03-14 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
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000089132 SCV000341659 pathogenic not provided 2018-07-20 criteria provided, single submitter clinical testing
Invitae RCV000409987 SCV000629221 pathogenic Phenylketonuria 2017-07-14 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs62507324, ExAC 0.001%). This variant has been reported in several individuals affected with phenylketonuria or mild hyperphenylalaninemia and in many of these cases it was found in combination with other PAH variants (PMID: 8860005, 8981952, 17096675, 19292873, 23430918, 23792259, 23942198, 24368688). This variant is also known as IVS7+3G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 102871). This variant has been observed in an individual with phenylalanine levels > 180 umol/L, findings that are highly specific for hyperphenylalaninemia (PMID: 19292873). Nucleotide substitutions within the consensus splice site are relatively common causes 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.

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