TSC1 Q654E - GET-Evidence

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Curation:
Currentness:

TSC1 Q654E

(TSC1 Gln654Glu)


Short summary

Found in three Southeast Asian individuals with Tuberous Sclerosis and in one fetus (later born live with cardiac rhabdomyoma). Case/control data has a significance of p = 0.08 (rare variant, needs more controls) and computational evidence does not support pathogenicity.

Variant evidence
Computational -1

gene associated with disease, polyphen=benign, NBLOSUM=-1, missense mutations usually not causative, and not conserved in mouse, drosophila or fungi. This is evaluated as contradicting evidence to a hypothesis of pathogenicity.

See Yamamoto T et al. 2002 (12015165), Choi JE et al. 2006 (16554133), unpublished research (below).

Functional -
Case/Control 1

significance = 0.08, OR estimated at 6.4

See Zhang H et al. 1999 (10570911), Yamamoto T et al. 2002 (12015165), Choi JE et al. 2006 (16554133), Milunsky A et al. 2009 (19254590), unpublished research (below).

Familial

Insufficient familial information, only one consistent segregation recorded (mother/child).

See Milunsky A et al. 2009 (19254590).

 
Clinical importance
Severity 4

Severe but highly variable

Treatability 1
Penetrance -
 

Impact

Insufficiently evaluated pathogenic

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

Inheritance pattern

dominant

Summary of published research, and additional commentary

LOVD (http://chromium.liacs.nl/LOVD2/TSC/variants.php?select_db=TSC1&action=search_all&order=Variant/DNA,ASC&hide_col=&show_col=&limit=100&search_pathogenic_=&search_Variant/Exon=&search_Variant/DNA=&search_Variant/DNA_published=&search_Variant/RNA=&search_Variant/Protein=Gln654Glu&search_Variant/DBID=&search_Variant/Origin=&search_Variant/DNA_remark=&search_Variant/Functional_Assay=&search_Variant/Amino_acid_PolyPhen=&search_Variant/Restriction_site=&search_Variant/Frequency=&search_Patient/Reference=&search_Patient/Detection/Template=&search_Patient/Detection/Technique=&search_Patient/Gender=&search_Patient/Origin/Geographic=&search_Patient/Origin/Ethnic=&search_Patient/Remarks=&search_Patient/Phenotype_2=&search_Patient/Times_Reported=) cites 5 reports, 4 of which claim no known pathogenicity and one claims pathogenic, and they conclude “no known pathogenicity”.

Total cases/controls case+ case– control+ control– p-value odds ratio
Tuberous Sclerosis 1
4 136 0 124 0.1249

 

Allele frequency

  • None available.

Publications
 

Zhang H, Nanba E, Yamamoto T, Ninomiya H, Ohno K, Mizuguchi M, Takeshita K. Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex. J Hum Genet. 1999;44(6):391-6. Erratum in: J Hum Genet 2000;45(4):269. PubMed PMID: 10570911.

In a screen for mutations in TSC1 and TSC2 in 38 Japanese individuals with Tuberous Sclerosis, this variant was found sporadically in a 21yo male with mental retardation, white macules, subependymal nodules and seizures. It was not seen in 60 normal Japanese controls.

Cases/controls case+ case– control+ control– p-value odds ratio
Tuberous Sclerosis 1
1 37 0 60 0.3878

 

Yamamoto T, Pipo JR, Feng JH, Takeda H, Nanba E, Ninomiya H, Ohno K. Novel TSC1 and TSC2 mutations in Japanese patients with tuberous sclerosis complex. Brain Dev. 2002 Jun;24(4):227-30. PubMed PMID: 12015165.

In a screen for TSC1 and TSC2 mutations in 9 Japanese individuals with tuberous sclerosis, this variant was seen as a compound heterozygote (with TSC2 R905W) in a 21yo female with neurological symptoms, dermatological lesions, brain radiological findings and a renal tumor. The variant was not seen in 64 Japanese and 55 Caucasian controls. This variant is reported as not causative due to the dearth of missense mutations in TSC1 causing tuberous sclerosis.

Cases/controls case+ case– control+ control– p-value odds ratio
Tuberous Sclerosis 1
1 8 0 64 0.1233

 

Choi JE, Chae JH, Hwang YS, Kim KJ. Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex. Brain Dev. 2006 Aug;28(7):440-6. Epub 2006 Mar 22. PubMed PMID: 16554133.

In a screen for TSC1 and TSC2 mutations in 44 Korean patients, this variant was seen in one familial case involving a female with white macules, seizures, renal cysts, cardiac rhabdomyoma and Cortical Tuber/subependymal nodule. Controls were not reported. The Gln variant is not conserved in mouse, drosophila or fungi.

Cases/controls case+ case– control+ control– p-value odds ratio
Tuberous Sclerosis 1
1 43 - - - -

 

Milunsky A, Ito M, Maher TA, Flynn M, Milunsky JM. Prenatal molecular diagnosis of tuberous sclerosis complex. Am J Obstet Gynecol. 2009 Mar;200(3):321.e1-6. PubMed PMID: 19254590.

In the development of a in utero diagnostic test for tuberous sclerosis, of 49 fetuses sampled this variant was reported in one mother and fetus of unknown ethnicity. The fetal ultrasound showed a cardiac rhabdomyoma which was confirmed upon live delivery.

Cases/controls case+ case– control+ control– p-value odds ratio
Tuberous Sclerosis 1
1 48 - - - -

 

Genomes
 

Other external references
 

    PolyPhen-2
  • Score: 0.063 (benign)
    Web search results (5 hits -- see all)
  • Why are some human disease-associated mutations fixed in mice?
    TSC1. NP_000359. Q654E. Primate-specific. No. 2. Lymphoma 10 (603517) BCL10 ... component of amyloid precursor; SGCA, sarcoglycan a; TSC1, tuberous sclerosis 1. ...
    umich.edu/~zhanglab/publications/.../Gao_2003_TIG_19_678.pdf
  • BMC Medical Genetics
    genes, TSC1 and TSC2, have been attributed to the development of TSC. ... Methods: Mutational analysis of TSC1 and TSC2 genes was performed in ...
    www.biomedcentral.com/content/pdf/1471-2350-7-72.pdf
  • Molecular and clinical analyses of 84 patients with tuberous ...
    Mutations in either one of 2 genes, TSC1 and TSC2, have been attributed to the ... Mutational analysis of TSC1 and TSC2 genes was performed in 84 Taiwanese TSC ...
    biomedcentral.com/content/download/xml/1471-2350-7-72.xml
  • [Analysis of gene mutation in patients with tuberous ...
    TSC1 and TSC2 are located on 9q34 and 16p13.3, respectively. ... Both TSC1 and TSC2 mutations were detected in 2 cases respectively. The same missense mutation (Q654E) was ...
    www.medscape.com/medline/abstract/14756965
  • An EcoRV polymorphism in exon 40 of the tuberous sclerosis 2 ...
    BioInfoBank Library :: An EcoRV polymorphism in exon 40 of the tuberous sclerosis 2 (TSC2) gene. Chimaerism shown by cytogenetics and DNA polymorphism analysis. The ...
    lib.bioinfo.pl/pmid:9076719

Other in silico analyses
 

  • NBLOSUM100 score = –2
  • GET-Evidence autoscore = 3

Edit history
 

Gene search

"GENE" or "GENE A123C":

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