PRPH D141Y - GET-Evidence

Curation:
Currentness:

PRPH D141Y

(PRPH Asp141Tyr)


Short summary

Hypothesized to cause ALS (or increased susceptibility) in a recessive manner, but this is based on a single observation and may lack statistical significance. The mutant protein appears to form abnormal aggregates.

Variant evidence
Computational -1

Polyphen 2 predicts benign effect

Functional 1

D141Y version of the protein forms aggregates

See Leung CL et al. 2004 (15446584).

Case/Control 4

p=.00175?

See Leung CL et al. 2004 (15446584).

Familial -
 
Clinical importance
Severity 4
Treatability 1
Penetrance 4

Unclear what the heritability is; ALS is not typically familial, but this particular case implied a recessive heritable version of the disease.

See Leung CL et al. 2004 (15446584).

 

Impact

High clinical importance, Uncertain pathogenic

(The "high 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

  • T @ chr12:49689404: 0.4% (33/9036) in EVS
  • Frequency shown in summary reports: 0.4% (33/9036)

Publications
 

Leung CL, He CZ, Kaufmann P, Chin SS, Naini A, Liem RK, Mitsumoto H, Hays AP. A pathogenic peripherin gene mutation in a patient with amyotrophic lateral sclerosis. Brain Pathol. 2004 Jul;14(3):290-6. PubMed PMID: 15446584.

The authors sequenced the PRPH gene in a cohort of 30 ALS patients, one of these (caucasian) was identified as homozygous for this variant. It was not seen in 100 caucasian control individuals.

Unsure how to calculate significance; the Fisher’s Exact test for case+: 2, case-: 58, control+: 0, control-: 200 is p=0.0526. However because the chances of both case+ occurring in the same individual out of 30 cases is much lower the significance is higher — perhaps (1 / 30) times the p-value = 0.00175.

The authors report that, in experiments with a transfected cell line with the D141Y variant gene, mutant peripherin was prone to form aggregates in
transfected cells.

Genomes
 

huB1FD55 - CGI sample GS01173-DNA_B07 from PGP sample 61499538
het T @ chr12:49689404

 

Other external references
 

    dbSNP
  • rs58599399
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • Score: 0.086 (benign)

Other in silico analyses
 

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 2

Edit history
 

Gene search

"GENE" or "GENE A123C":

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