ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.331C>T (p.Arg111Ter) (rs76296470)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000000611 SCV000852165 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Nonsense variant; PP4_Moderate: Seen in multiple Chinese PKU patients. BH4 deficiency excluded. (PMID:1301187; PMID:2816939; PMID:9860305); PM3: Detected with R243Q, pathogenic in ClinVar (PMID:15503242). In summary this variant meets criteria to be classified as pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PVS1, PP4_Moderate, PM3).
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000088898 SCV000228838 pathogenic not provided 2015-02-18 criteria provided, single submitter clinical testing
Invitae RCV000000611 SCV000629190 pathogenic Phenylketonuria 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg111*) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs76296470, ExAC 0.03%). This variant has been reported in multiple individuals from different ethnic groups affected with phenylketonuria (PMID: 12542580, 24401910, 16256386, 27121329, 21307867). ClinVar contains an entry for this variant (Variation ID: 581). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000000611 SCV000893952 pathogenic Phenylketonuria 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000000611 SCV000919917 pathogenic Phenylketonuria 2018-08-03 criteria provided, single submitter clinical testing Variant summary: PAH c.331C>T (p.Arg111X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 3.2e-05 in 246200 control chromosomes (gnomAD). The variant, c.331C>T, has been reported in the literature in multiple individuals affected with Phenylalanine Hydroxylase Deficiency (Phenylketonuria)(Tao_2015, Tyfield_1995). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000000611 SCV000020761 pathogenic Phenylketonuria 1990-05-01 no assertion criteria provided literature only
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088898 SCV000119496 not provided not provided no assertion provided not provided
Counsyl RCV000000611 SCV000485304 pathogenic Phenylketonuria 2016-01-21 no assertion criteria provided clinical testing

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