PAH R408W - 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 R408W

(PAH Arg408Trp)


Short summary

The PAH-R408W allele is commonly found in clinical cases of phenylketonuria (PKU) identified by newborn screening. This allele makes up about 20% of mutant PAH alleles found in clinical cases of PKU in eastern Europe. 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-R408W to be PROBABLY DAMAGING with a score of 1.000 (sensitivity: 0.00; specificity: 1.00).

Functional -
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

  • A @ chr12:103234271: 0.1% (14/10758) in EVS
  • Frequency shown in summary reports: 0.1% (14/10758)

Publications
 

Jaruzelska J, Henriksen KF, Güttler F, Riess O, Borski K, Blin N, Slomski R. The codon 408 mutation associated with haplotype 2 is predominant in Polish families with phenylketonuria. Hum Genet. 1991 Jan;86(3):247-50. PubMed PMID: 1671768.

“Among 43 fully-informative families 16 RFLP haplotypes were identified. Haplotype 2 is the most frequently (62%) associated with Polish PKU alleles, and the codon 408 mutation is in complete linkage disequilibrium with this haplotype in Poland.”

DiLella AG, Marvit J, Brayton K, Woo SL. An amino-acid substitution involved in phenylketonuria is in linkage disequilibrium with DNA haplotype 2. Nature. 1987 May 28-Jun 3;327(6120):333-6. PubMed PMID: 2884570.

“We now report the molecular lesion associated with the RFLP haplotype 2 mutant allele. This defect is caused by a C-to-T transition in exon 12 resulting in an amino-acid substitution (Arg to Trp) at residue 408 of PAH. Direct hybridization analysis of the point mutation using a specific oligonucleotide probe demonstrated that this mutation is also in linkage disequilibrium with RFLP haplotype 2 alleles that make up about 20% of mutant PAH genes.”

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 = 7
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

Log in