ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.694C>T (p.Gln232Ter)

gnomAD frequency: 0.00001  dbSNP: rs62507348
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169464 SCV001370877 pathogenic Phenylketonuria 2020-05-31 reviewed by expert panel curation The c.694C>T (p.Gln232Ter) variant in PAH has been reported in multiple individuals with PKU (PP4; PMID: 30050108). This variant has an extremely low allele frequency (MAF=0.00003; PM2). This variant was detected with known pathogenic variant c.442-1G>A (PM3; PMID: 30050108). This is a null variant (nonsense) in exon 6 of 13 (NMD predicted) of PAH, a gene where loss of function is a known mechanism of disease (PVS1). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3, PP4.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000089039 SCV000601715 pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000169464 SCV001386850 pathogenic Phenylketonuria 2023-11-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln232*) in the PAH gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). This variant is present in population databases (rs62507348, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with PAH-related conditions (PMID: 16256386, 23932990, 25087612, 26600521, 27264808, 29390883). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 102788). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000089039 SCV000119644 not provided not provided no assertion provided not provided
Counsyl RCV000169464 SCV000220898 pathogenic Phenylketonuria 2019-06-10 no assertion criteria provided clinical testing
Natera, Inc. RCV000169464 SCV002088648 pathogenic Phenylketonuria 2020-09-11 no assertion criteria provided clinical testing

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