SPG7 R688Q - GET-Evidence

Note: This variant has not been sufficiently evaluated by a GET-Evidence editor.

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Curation:
Currentness:

SPG7 R688Q

(SPG7 Arg688Gln)


Short summary

The SPG7 gene (spastic paraplegia 7) encodes the mitochondrial protein paraplegin. Mutations in this gene are associated with hereditary spastic paraplegia (HSP), which is characterized by progressive stiffness and weakness in the lower limbs. The gene is located on Chromosome 16 and consists of 17 exons spanning 52kb. This is the only gene in which mutations are known to cause hereditary spastic paraplegia. Alleles are inherited in an autosomal recessive manner. The R688Q mutation is a single nucleotide polymorphism at exon 15. The polymorphism changes the ancestral allele, G, to an A at base pair 2063. This allele is also known as rs12960, which was shown to be associated with toxicity responses to chemotherapy drugs such as Docetaxel.

Variant evidence
Computational 2

This variant has a PolyPhen score of 0.203 (possibly damaging) and other variants also are known to cause HSP.

See Wilkinson PA et al. 2004 (14985266).

Functional

No evidence.

Case/Control 4

p-value of 0.004 for the association of rs12960 with toxicity to chemotherapy drugs.

See Deeken JF et al. 2009 (20038957).

Familial

No evidence.

 
Clinical importance
Severity 3

HSP moderately affects a patient’s quality of life, although the association with toxicity to chemotherapy drugs might be more severe.

Treatability 3

Some drugs are available to reduce spasticity and muscle tightness in HSP.

See 20301286.

Penetrance -
 

Impact

Insufficiently evaluated pharmacogenetic

(The "insufficiently evaluated" qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern

recessive

Summary of published research, and additional commentary

 

Unpublished cases/controls case+ case– control+ control– p-value odds ratio
Spastic Paraplegia 7
5 65 24 76 0.0038 0.244

 

Total cases/controls case+ case– control+ control– p-value odds ratio
Spastic Paraplegia 7
5 65 24 76 0.0038 0.244

 

Allele frequency

  • A @ chr16:89620328: 14.2% (1528/10756) in EVS
  • A @ chr16:88147828: 14.1% (18/128) in GET-Evidence
  • Frequency shown in summary reports: 14.2% (1528/10756)

Publications
 

Wilkinson PA, Crosby AH, Turner C, Bradley LJ, Ginsberg L, Wood NW, Schapira AH, Warner TT. A clinical, genetic and biochemical study of SPG7 mutations in hereditary spastic paraplegia. Brain. 2004 May;127(Pt 5):973-80. Epub 2004 Feb 25. Erratum in: Brain. 2004 Sep;127(Pt 9):2148. PubMed PMID: 14985266.

 

Deeken JF, Cormier T, Price DK, Sissung TM, Steinberg SM, Tran K, Liewehr DJ, Dahut WL, Miao X, Figg WD. A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform. Pharmacogenomics J. 2009 Dec 29. [Epub ahead of print] PubMed PMID: 20038957.

 

Casari G, Marconi R. Spastic Paraplegia 7. 2006 Aug 24 [updated 2010 Dec 23]. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-. Available from http://www.ncbi.nlm.nih.gov/books/NBK1107/ PubMed PMID: 20301286.

 

Genomes
 

hu011C57 - CGI sample GS01669-DNA_B05 from PGP sample 86486261
het A @ chr16:89620328

 

hu025CEA - CGI sample GS01669-DNA_D02 from PGP sample 27316983
het A @ chr16:89620328

 

 

hu2DBF2D - CGI sample GS01173-DNA_G02 from PGP sample 67180598
het A @ chr16:89620328

 

hu342A08 - CGI sample GS01175-DNA_B05 from PGP sample 83494370
hom A @ chr16:89620328

 

 

hu38168C - CGI sample GS01173-DNA_H06 from PGP sample 91708424
het A @ chr16:89620328

 

hu43860C - CGI sample GS00253-DNA_A01_200_37
het A @ chr16:89620328

 

hu72A81D - CGI sample GS01173-DNA_C02 from PGP sample 10366372
het A @ chr16:89620328

 

hu8229AE - CGI sample GS01173-DNA_A07 from PGP sample 96240009
het A @ chr16:89620328

 

hu92C40A - CGI sample GS01175-DNA_G03 from PGP sample 92527586
het A @ chr16:89620328

 

hu9385BA - CGI sample GS00253-DNA_E01_200_37
hom A @ chr16:89620328

 

huA0E089 - CGI sample GS01175-DNA_B04 from PGP sample 88590671
het A @ chr16:89620328

 

 

huAE6220 - CGI sample GS00253-DNA_H01_200_37
het A @ chr16:89620328

 

huBAAC98 - CGI sample GS01173-DNA_F02 from PGP sample 70008981
het A @ chr16:89620328

 

huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr16:89620328

 

huCA017E - CGI sample GS01175-DNA_B01 from PGP sample 86206034
het A @ chr16:89620328

 

huE80E3D - CGI sample GS00253-DNA_D01_200_37
het A @ chr16:89620328

 

GS06994 - var-GS06994-1100-36-ASM
het A @ chr16:88147829

 

GS10851 - var-GS10851-1100-36-ASM
het A @ chr16:88147829

 

GS18940 - var-GS18940-1100-36-ASM
het A @ chr16:88147829

 

GS18942 - var-GS18942-1100-36-ASM
het A @ chr16:88147829

 

GS19701 - var-GS19701-1100-36-ASM
het A @ chr16:88147829

 

GS19704 - var-GS19704-1100-36-ASM
het A @ chr16:88147829

 

GS20509 - var-GS20509-1100-36-ASM
het A @ chr16:88147829

 

NA12878

 

Other external references
 

    dbSNP
  • rs12960
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PharmGKB
  • [Prostatic Neoplasms]
    [docetaxel; thalidomide]
    Risk or phenotype-associated allele: G Phenotype: The SPG7:rs12960 G variant was associated with toxicity in response to docetaxel and thalidomide. Study size: 47 Study population/ethnicity: Patients diagnosed with castration-resistant prostate cancer enrolled in a randomized phase II clinical trial comparing docetaxel to docetaxel with thalidomide. Significance metric(s): p = 0.004 Type of association: CO; TOX
    www.ncbi.nlm.nih.gov/pubmed/20038957
    PolyPhen-2
  • Score: 0.203 (possibly damaging)
    Web search results (4 hits -- see all)
  • A clinical, genetic and biochemical study of SPG7 mutations ...
    Mutations in the SPG7 gene, encoding the mitochon- drial protein paraplegin, were the ® ... of the SPG7 gene were screened for mutations using a. combination of ...
    brain.oxfordjournals.org/cgi/reprint/awh125v1.pdf
  • Table 3 Text
    ... total chromosomes genotyped MAF mean MAF stdev chromosomes genotyped ... criterion prediction score number sequences aligned prediction score divergence ...
    icr.ac.uk/research/research_sections/.../2842.txt
  • Type III 97%
    ... SWISS-PROT ID Variant site Phosphorylation site SWISS-PROT variant ID ... Reference(s) for variant Reference(s) for phosphorylation site TPSD1 Q9BZJ3 P15R ...
    nih.go.kr/phosphovariant/html/family_whole/TypeIII_97.txt

Other in silico analyses
 

  • NBLOSUM100 score = 0
  • GET-Evidence autoscore = 4

Edit history
 

Gene search

"GENE" or "GENE A123C":

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