PAH R158Q - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

To be considered sufficiently evaluated a variant must have both "variant evidence" and "clinical importance" scores filled in.

Please help improve GET-Evidence by evaluating evidence for this variant!

Curation:
Currentness:

PAH R158Q

(PAH Arg158Gln)


Short summary

The PAH-R158Q allele was identified in a patient with phenylketonuria. The effect of this allele on enzyme function was demonstrated in a mammalian cell assay system. If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia.

Variant evidence
Computational 1

PolyPhen-2 predicts PAH-R158Q to be PROBABLY DAMAGING with a score of 1.000 (sensitivity: 0.00; specificity: 1.00).

Functional 1

“Expression analysis in heterozygous mammalian cells after site-directed mutagenesis demonstrated that the Arg158-to-Gln158 mutation is a PKU mutation, whereas the Arg261-to-Gln261 mutation is apparently silent in the assay system.”

See Okano Y et al. 1990 (1967207).

Case/Control -
Familial -
 
Clinical importance
Severity 4

If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia.

See Zurflüh MR et al. 2008 (17935162).

Treatability 5

“Following the introduction 30 years ago of neonatal screening and early dietary treatment for phenylketonuria there has been a dramatic decrease in the severity of neurological dysfunction associated with this disorder.”

See Thompson AJ et al. 1993 (8353710).

Penetrance -
 

Impact

Insufficiently evaluated pathogenic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr12:103260410: 0.0% (2/10758) in EVS
  • Frequency shown in summary reports: 0.0% (2/10758)

Publications
 

Okano Y, Wang T, Eisensmith RC, Steinmann B, Gitzelmann R, Woo SL. Missense mutations associated with RFLP haplotypes 1 and 4 of the human phenylalanine hydroxylase gene. Am J Hum Genet. 1990 Jan;46(1):18-25. PubMed PMID: 1967207; PubMed Central PMCID: PMC1683547.

“Expression analysis in heterozygous mammalian cells after site-directed mutagenesis demonstrated that the Arg158-to-Gln158 mutation is a PKU mutation, whereas the Arg261-to-Gln261 mutation is apparently silent in the assay system.”

Thompson AJ, Tillotson S, Smith I, Kendall B, Moore SG, Brenton DP. Brain MRI changes in phenylketonuria. Associations with dietary status. Brain. 1993 Aug;116 ( Pt 4):811-21. PubMed PMID: 8353710.

“Following the introduction 30 years ago of neonatal screening and early dietary treatment for phenylketonuria there has been a dramatic decrease in the severity of neurological dysfunction associated with this disorder. However, there is evidence that subtle neurological impairment remains common in early treated subjects and in the last 3 years there have been a number of reports of overt neurological impairment with white matter abnormalities on MRI...These data are consistent with studies in animals showing that hyperphenylalaninaemia increases myelin turnover in a dose dependent manner. It is suggested that the effects of phenylalanine on myelin pose a lifelong hazard to the nervous system.”

Zurflüh MR, Zschocke J, Lindner M, Feillet F, Chery C, Burlina A, Stevens RC, Thöny B, Blau N. Molecular genetics of tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency. Hum Mutat. 2008 Jan;29(1):167-75. PubMed PMID: 17935162.

If undiagnosed and untreated, phenylketonuria can result in impaired postnatal cognitive development resulting from a neurotoxic effect of hyperphenylalaninemia.

Genomes
 

Other external references
 

    PolyPhen-2
  • Score: 1.0 (probably damaging)

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in