FAH R341W - GET-Evidence

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Curation:
Currentness:

FAH R341W

(FAH Arg341Trp)


Short summary

This variant shows pseudodeficiency for production of FAH protein which is connected with hereditary tyrosinemia type I. Pseudodeficiency was confirmed with site-directed mutagenesis and expression in a rabbit reticulocyte lysate system. The allelic frequency in 516 Norwegian controls was 0.022.

Variant evidence
Computational 1

Other variants cause disease which this mutation imitates.

See unpublished research (below).

Functional 1

See unpublished research (below).

Case/Control 5

Very significant case/control.

See Rootwelt H et al. 1994 (7977370), unpublished research (below).

Familial

See unpublished research (below).

 
Clinical importance
Severity

See unpublished research (below).

Treatability -
Penetrance -
 

Impact

Low clinical importance, Likely benign

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

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Allele frequency

  • T @ chr15:80472526: 1.7% (186/10758) in EVS
  • Frequency shown in summary reports: 1.7% (186/10758)

Publications
 

Rootwelt H, Brodtkorb E, Kvittingen EA. Identification of a frequent pseudodeficiency mutation in the fumarylacetoacetase gene, with implications for diagnosis of tyrosinemia type I. Am J Hum Genet. 1994 Dec;55(6):1122-7. PubMed PMID: 7977370; PubMed Central PMCID: PMC1918441.

This variant shows pseudodeficiency for production of FAH protein. Three different individuals/families with pseudodeficiency were confirmed to have this allele (one homozygous, two compound heterozygous); This finding was confirmed with site-directed mutagenesis and expression in a rabbit reticulocyte lysate system. The allelic frequency in 516 Norwegian controls was 0.022 (23 out of 1032 chromosomes). case+: 4, case-: 2, control+: 23, control-: 1009. significance = 5.3 * 10^-6, OR = 88.

Genomes
 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het T @ chr15:80472526

 

hu3CAB43 - CGI sample GS01175-DNA_D03 from PGP sample 27486199
het T @ chr15:80472526

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het T @ chr15:80472526

 

Other external references
 

    dbSNP
  • rs11555096
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.997 (probably damaging)
    Web search results (18 hits -- see all)
  • 3445 - Tyrosinemia Type 1 - FAH Sequencing - Mitochondrial ...
    FAH deficiency causes tyrosinemia type 1, an autosomal recessive ... The FAH gene has a "pseudodeficiency" allele, e.g. R341W, which results in normal amount ...
    www.bcm.edu/geneticlabs/tests/mito/FAH.html
  • Structural and functional analysis of missense mutations in ...
    Mutated FAH proteins were expressed in Escherichia coli and in mammalian CV-1 cells. ... to enzymatically inactive FAH proteins. Two mutations (R341W, associated with the pseudo ...
    www.ncbi.nlm.nih.gov/pubmed/11278491
  • BioMed Central | Full text | A missense mutation (Q279R) in ...
    No FAH was found in tumor regions while a healthy region contained enzyme-expressing ... (R341W) causes a pseudodeficient phenotype with a reduced amount of FAH immunoreactive ...
    www.biomedcentral.com/1471-2156/2/9
  • A missense mutation (Q279R) in the Fumarylacetoacetate ...
    No FAH was found in tumor regions while a healthy region contained enzyme-expressing ... (R341W) causes a pseudodeficient phenotype with a reduced amount of FAH immunoreactive ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC35353
  • A missense mutation (Q279R) in the Fumarylacetoacetate ...
    No FAH was found in tumor regions while a healthy region contained enzyme ... (R341W) causes a pseudodeficient phenotype. with a reduced amount of FAH immunoreactive ...
    www.biomedcentral.com/content/pdf/1471-2156-2-9.pdf
  • Amplified DNA Nanoarray Sequencing
    FAH. R341W. FAH deficiency. Is a pseudodeficiency allele for FAH and is ... heterozygotes with FAH. deficiency (S15). Het. 16. 3244464. MEFV. R202Q. FMF ...
    www.sciencemag.org/cgi/data/1181498/DC1/1
  • Sup.doc
    FAH. R341W. FAH deficiency. Is a pseudodeficiency allele for FAH and is ... heterozygotes with FAH deficiency (S15). Het. 16. 3244464. MEFV. R202Q. FMF ...
    arep.med.harvard.edu/pdf/Drmanac_sup_09.doc
  • Structural and functional analysis of missense mutations in ...
    ... autosomal recessive disease caused by a deficiency of the enzyme involved in the last step of tyrosine degradation, fumarylacetoacetate hydrolase (FAH) ...
    www.medscape.com/medline/abstract/11278491?prt=true
  • PubMed: 11278491
    Mutated FAH proteins were expressed in Escherichia coli and in mammalian CV-1 cells. ... to enzymatically inactive FAH proteins. Two mutations (R341W, associated with the pseudo ...
    www.genome.jp/dbget-bin/www_bget?pubmed+11278491

Other in silico analyses
 

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

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