ClinVar Miner

Submissions for variant NM_000277.3(PAH):c.1089del (p.Lys363fs) (rs5030654)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen PAH Variant Curation Expert Panel RCV000169397 SCV000852154 pathogenic Phenylketonuria 2018-08-10 reviewed by expert panel curation PAH-specific ACMG/AMP criteria applied: PVS1: Frameshift variant; PM2: Absent from ExAC, gnomAD, 1000G, ESP; PP4: Detected in a patient with Classical PKU. (PMID:8659548). 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, PM2, PP4).
Counsyl RCV000169397 SCV000220793 likely pathogenic Phenylketonuria 2014-10-14 criteria provided, single submitter literature only
GeneDx RCV000088751 SCV000568713 pathogenic not provided 2017-01-24 criteria provided, single submitter clinical testing The c.1089delG variant in the PAH gene has been reported as a pathogenic variant in the PAH Consortium database. The c.1089delG variant has been reported previously in association with a classic phenylketonuria (PKU) phenotype when present in the homozgyous state or when present with another variant associated with classic PKU (Alibakhshi et al. 2014; Bercovich et al. 2008). The c.1089delG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1089delG deletion causes a frameshift starting with codon Lysine 363, changes this amino acid to an Asparagine residue and creates a premature Stop codon at position 37 of the new reading frame, denoted p.Lys363NfsX37. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.1089delG to be a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000169397 SCV000696425 pathogenic Phenylketonuria 2016-10-14 criteria provided, single submitter clinical testing Variant summary: The PAH c.1089delG (p.Lys363Glnfs) variant results in a premature termination codon, predicted to cause a truncated or absent PAH protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant has been reported in numerous PKU and HPA patients and is absent in 121252 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic. Taken together, this variant is classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000088751 SCV000889561 pathogenic not provided 2018-01-14 criteria provided, single submitter clinical testing
Invitae RCV000169397 SCV000943570 pathogenic Phenylketonuria 2018-08-10 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys363Asnfs*37) in the PAH gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with other PAH variants in individuals affected with phenylketonuria (PMID: 8889590, 20920871,  21890392, 24048906). ClinVar contains an entry for this variant (Variation ID: 102518). Loss-of-function variants in PAH are known to be pathogenic (PMID: 1301187, 9634518). For these reasons, this variant has been classified as Pathogenic.
DeBelle Laboratory for Biochemical Genetics, MUHC/MCH RESEARCH INSTITUTE RCV000088751 SCV000119335 not provided not provided no assertion provided not provided

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