ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.168+5G>A

dbSNP: rs62507288
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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 RCV000666582 SCV001146713 likely pathogenic Phenylketonuria 2019-05-26 reviewed by expert panel curation The c.168+5G>A variant has been identified in at least 4 probands with phenotypes ranging from mild HPA to classic PKU, with at least 2 probands excluding BH4 deficiency (PMIDs: 9429153, 26413448, 27121329). It has been detected in the homozygous form (PMID: 26413448) as well as in trans with pathogenic variants R297H (PMID: 9429153), I65T, and S349P (PMID: 27121329). This variant is absent from 1000G, ESP, and gnomAD databases. Computational analysis predicts an alteration of the WT donor site, most probably affecting splicing. 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 RCV000666582 SCV000790893 likely pathogenic Phenylketonuria 2018-05-15 criteria provided, single submitter clinical testing
Mendelics RCV000666582 SCV001138805 pathogenic Phenylketonuria 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000666582 SCV004296193 pathogenic Phenylketonuria 2023-05-26 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 102605). This variant is also known as IVS2+5G>A. This variant has been observed in individual(s) with hyperphenylalaninemia (PMID: 9429153, 29288420, 33465300). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 2 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.168+5G nucleotide in the PAH gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 8364593, 21890392, 22330942, 22526846). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088847 SCV000119442 not provided not provided no assertion provided not provided

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