ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.969+5G>A

dbSNP: rs62508637
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV001093511 SCV001250542 pathogenic Phenylketonuria 2019-12-22 reviewed by expert panel curation The c.969+5G>A variant in PAH has been reported in at least 4 individuals with classic PKU (BH4 deficiency excluded) (PP4_moderate; PMID: 24048906). This variant is absent in population databases (PM2). This variant has been detected in the homozygous state and in compound heterozygotes with at least 6 Pathogenic/Likely Pathogenic variants including A300S (ClinVar: 92751, Pathogenic), R176X (ClinVar: 102723, Pathogenic), c.168+5G>C (ClinVar 102606, Pathogenic), and c.913-7A>G (ClinVar: 102894, Likely Pathogenic), c.1066-11G>A (ClinVar: 607, Pathogenic), E280K (ClinVar 580, Pathogenic) (PM3_VeryStrong; PMID: 30159852, PMID:10947211, PMID:24048906, PMID:30389586, PMID:24368688). Computational prediction tools suggest that c.969+5G>A may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP3, PP4_Moderate.
Labcorp Genetics (formerly Invitae), Labcorp RCV001093511 SCV002242981 pathogenic Phenylketonuria 2024-04-03 criteria provided, single submitter clinical testing This sequence change falls in intron 9 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 individual(s) with hyperphenylalaninemia (PMID: 10947211, 24368688, 26413448, 28676969, 29892150). This variant is also known as IVS9+5G>A. ClinVar contains an entry for this variant (Variation ID: 102915). 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.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089181 SCV000119796 not provided not provided no assertion provided not provided

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