PAH V245A - GET-Evidence

Curation:
Currentness:

PAH V245A

(PAH Val245Ala)


Short summary

This variant was found in combination with some other PAH variants in a few Danish cases of hyperphenylalaninemia. The mildly elevated phenylalanine levels of these cases are generally considered benign, dietary intervention is not usually recommended.

Variant evidence
Computational -
Functional -
Case/Control 4

p = 0.00095

See Guldberg P et al. 1994 (8088845).

Familial -
 
Clinical importance
Severity 1

Hyperphenylalaninemia of less than 6 mg/dL (as in Guldberg et al’s patients) is considered benign

Treatability

No dietary intervention recommended

Penetrance 5

No report of variant in controls

 

Impact

Low clinical importance, Uncertain pathogenic

(The "low clinical importance, uncertain" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • G @ chr12:103246701: 0.1% (7/10758) in EVS
  • G @ chr12:101770830: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.1% (7/10758)

Publications
 

Guldberg P, Henriksen KF, Thöny B, Blau N, Güttler F. Molecular heterogeneity of nonphenylketonuria hyperphenylalaninemia in 25 Danish patients. Genomics. 1994 May 15;21(2):453-5. PubMed PMID: 8088845.

This variant was seen heterozygously (in combination with another variant in the same gene) in 3 out of 25 cases of hyperphenylalanimemia — phenylalanine concentrations in blood which are above the reference range but below what is considered diagnostic of phenylketonuria. The authors refer to 220 “normal chromosomes” from documented carriers as a control, with none of these carrying the variant. This could be summarized as case+: 3, case-: 22, cont+: 0, cont-: 220. This has a p-value of 0.00095.

Guldberg P, Rey F, Zschocke J, Romano V, François B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Güttler F. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet. 1998 Jul;63(1):71-9. Erratum in: Am J Hum Genet 1998 Oct;63(4):1252-3. PubMed PMID: 9634518; PubMed Central PMCID: PMC1377241.

This review classifies the variant as causing mild hyperphenylalaninemia

Genomes
 

hu0D879F - CGI sample GS00253-DNA_G01_200_37
het G @ chr12:103246701

 

Other external references
 

    dbSNP
  • rs76212747
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.976 (probably damaging)
    Web search results (88 hits -- see all)
  • Mutations Detected in Patients with BH4-responsive PAH Deficiency
    BH4-responsive PAH Deficiency. blue = mutations with residual activity (measured or ... V245A. R243X. R243Q. R241H. R241C. P211T. V190A. V177M. H170Q. R158W. R158Q ...
    www.bh4.org/biopkudocs/PAH_domains.pdf
  • PAH : Phenylalanine Hydroxylase Locus Knowledgebase web site
    PAH Phenylalanine Hydroxylase Locus Specific Database,Medical Genetics, McGill University Health Centre
    www.pahdb.mcgill.ca/?Topic=About&Section=CuratorsPage&Page=0
  • Mutation at the phenylalanine hydroxylase gene (PAH) and its ...
    Mutation at the phenylalanine hydroxylase gene (PAH) and its use to document population ... because of intragenic recombination (S67P, G218V, V245A and IVS12nt1) ...
    www.nature.com/ejhg/journal/v6/n1/abs/5200153a.html
  • 13 1 2 3 4 5 6 7 8 9 10 11 12 Introns Exons
    V245A. R243Q. R243X. R241C. R241H. A300S. K320N. P314S. A313T. S310Y. A309V ... Mutations with residual PAH activity (potentially BH4-responsive) Mutations associated ...
    www.biopku.org/biopkudocs/biopku_pah_map.pdf
  • The metabolic and molecular bases of tetrahydrobiopterin ...
    alytic domain of PAH, 21% in the regulatory domain, 5% (4 mutations) ... binding regions CBR1 (V245A, R252W, R261X, and. R261Q) and CBR2 (P281A, P281S, and P281L) ...
    www.bh4.org/pdf/blau_erlandsen.pdf
  • Human Phenylalanine Hydroxylase Mutations and ...
    PAH Mutation Analysis Consortium Database, on 365. patients harboring 73 different PAH ... sible for HPA map to the PAH locus, some occur at loci. controlling ...
    sciencedirect.com/science?_ob=MImg&...&ie=/sdarticle.pdf
  • A molecular survey of phenylketonuria in Lithuania: spectrum ...
    We report the spectrum of the PAH gene mutations in individuals ... Twenty-one different PAH gene mutations were. identified in Lithuania, resulting in an ...
    images.katalogas.lt/maleidykla/bio23/B-60.pdf
  • Incidence of BH
    responsiveness among a non-selected, cohort population of PAH-de ... A403V. MHP. 88.7. 61. S411X. D415N. MHP. 78.3. 64. V245A. A403V. MHP. 91.2. 65. R261Q. V245A. MHP. 83.0 ...
    www.biopku.org/pdf/fioriMGM.pdf
  • IVE-Human
    PAHdb Advanced Search ... p.V245A. 2. p.V245E. 2. p.V245L. 2. p.D282N. 2. p.I283F. 2. p.I306V. 2. p.A342T. 2. p.A395P. 2. p.D415N. 2. p.I318T. 2. p.Y277D. 2. IVS10-11G>A. 2. p.P122Q. 2. p.A309V. 2. p. ...
    www.pahdb.mcgill.ca/PahdbSearch.php?MenuSelection=IVE-Human
  • FINDbase
    Phenylketonuria. c.692C>T. PAH. Phenylketonuria. c.696A>G. PAH. Phenylketonuria ... p.V245A. PAH. Phenylketonuria. p.V245E. PAH. Phenylketonuria. p.V245L. PAH. Phenylketonuria. p. ...
    findbase.org/display-file.php?...&consortium=

Other in silico analyses
 

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

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