PRF1 A91V - GET-Evidence



(PRF1 Ala91Val)

Short summary

This variant may be associated with a slightly increased susceptibility to some rare blood disorders, in particular autoimmune proliferative disease, if combined with a more severe mutation elsewhere. Most reports lack statistical significance.

Variant evidence
Computational 1

Polyphen2 predicts damaging effect

Functional 1

Reduction in cytotoxic function

See Voskoboinik I et al. 2007 (17475905).

Case/Control 3

p = 0.0165

See Clementi R et al. 2006 (16720836).


No familial data

Clinical importance
Severity 4
Treatability 4
Penetrance 1

See Clementi R et al. 2006 (16720836).



Low clinical importance, Likely pathogenic

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

Inheritance pattern


Summary of published research, and additional commentary


Allele frequency

  • A @ chr10:72360387: 3.3% (350/10758) in EVS
  • A @ chr10:72030392: 2.4% (3/126) in GET-Evidence
  • Frequency shown in summary reports: 3.3% (350/10758)


Clementi R, Chiocchetti A, Cappellano G, Cerutti E, Ferretti M, Orilieri E, Dianzani I, Ferrarini M, Bregni M, Danesino C, Bozzi V, Putti MC, Cerutti F, Cometa A, Locatelli F, Maccario R, Ramenghi U, Dianzani U. Variations of the perforin gene in patients with autoimmunity/lymphoproliferation and defective Fas function. Blood. 2006 Nov 1;108(9):3079-84. Epub 2006 May 23. PubMed PMID: 16720836.

In a study of Autoimmune Lymphoproliferative Disease (ALD), 28 patients with Dianzani ALD (DALD) were screened for variants in PRF1. This variant was seen more often in these cases than in the 816 controls: case var/var: 1, case var/wt: 5, case wt/wt: 22, cont var/var: 3, cont var/wt: 69, cont wt/wt: 744. The allele frequency difference between the cases and controls has a significance of p = 0.0165.

According to Orphanet this is a “rare disease” with an incidence of less than 1 in 2000. From this we estimate that if this variant causes an increased susceptibility to this disease, the attributable increased risk is still less than 1%.

Solomou EE, Gibellini F, Stewart B, Malide D, Berg M, Visconte V, Green S, Childs R, Chanock SJ, Young NS. Perforin gene mutations in patients with acquired aplastic anemia. Blood. 2007 Jun 15;109(12):5234-7. Epub 2007 Feb 20. PubMed PMID: 17311987; PubMed Central PMCID: PMC1890825.

DNA from 75 unrelated patients with acquired aplastic anemia were sequenced for PRF1. Of these, three were heterozygous for this A91V variant. The authors report studying >1000 individuals and find an allele frequency of 1%, without much variation between ethnic groups. Their observation of this variant in the patients is not significant — the authors report a p-value of 0.27.

Voskoboinik I, Sutton VR, Ciccone A, House CM, Chia J, Darcy PK, Yagita H, Trapani JA. Perforin activity and immune homeostasis: the common A91V polymorphism in perforin results in both presynaptic and postsynaptic defects in function. Blood. 2007 Aug 15;110(4):1184-90. Epub 2007 May 2. PubMed PMID: 17475905.

These authors claim an alele frequency of 8-9% (no citation or data given). Investigating the effect of this variant in cytotoxic T lymphocytes found that cells expressing this variant had about half cytotoxicity compared to wild type. The purified proteins, when tested directly on target cells, had a more pronounced reduction in cytotoxic function (>10-fold).


huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr10:72360387


huD37D14 - CGI sample GS01175-DNA_A04 from PGP sample 13272228
het A @ chr10:72360387


GS19649 - var-GS19649-1100-36-ASM
het A @ chr10:72030393


GS19735 - var-GS19735-1100-36-ASM
het A @ chr10:72030393


Other external references

  • rs35947132
  • GeneTests records for the PRF1 gene
    Aplastic Anemia
    Familial Hemophagocytic Lymphohistiocytosis
    Familial Hemophagocytic Lymphohistiocytosis 2
  • Score: 0.852 (probably damaging)

Other in silico analyses

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

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Gene search

"GENE" or "GENE A123C":

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