TSC1 M224R - GET-Evidence

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Curation:
Currentness:

TSC1 M224R

(TSC1 Met224Arg)


Short summary

 

Variant evidence
Computational -
Functional -
Case/Control -
Familial -
 
Clinical importance
Severity -
Treatability -
Penetrance 5

This mutation was found in two generations of one family, all of whom previously had a definite diagnosis of TSC.

 

Impact

Insufficiently evaluated pathogenic

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

Inheritance pattern

unknown

Summary of published research, and additional commentary

 

Allele frequency

  • None available.

Publications
 

Nellist M, van den Heuvel D, Schluep D, Exalto C, Goedbloed M, Maat-Kievit A, van Essen T, van Spaendonck-Zwarts K, Jansen F, Helderman P, Bartalini G, Vierimaa O, Penttinen M, van den Ende J, van den Ouweland A, Halley D. Missense mutations to the TSC1 gene cause tuberous sclerosis complex. Eur J Hum Genet. 2009 Mar;17(3):319-28. doi: 10.1038/ejhg.2008.170. Epub 2008 Oct 1. PubMed PMID: 18830229; PubMed Central PMCID: PMC2986174.

In this study, they sampled individuals from one family who had already a definite diagnosis of TSC. All the affected individuals in the family were heterozygous for the mutation M224R cosegregated with the mutation G1035S. A functional analysis showed that only the mutation M224R was responsible for the different phenotypes presented by the patients, such as seizures, cortical tubers, below-average intelligence, skin lessons, and epilepsy, by a problem in the regulation pathway of p70 S6 Kinase and ribosomal protein.

Genomes
 

Other external references
 

    PolyPhen-2
  • Score: 1.0 (probably damaging)
    Web search results (12 hits -- see all)
  • Supplemental Figure Legends
    Functional analysis of the pathogenic TSC1 M224R amino acid substitution. ... The M224R-G1035S double variant was also expressed at low levels and did not ...
    neurology.org/content/vol0/issue2007/.../DC1/EFigLegends.doc
  • Bladder tumour-derived somatic TSC1 missense mutations cause ...
    Bladder tumour-derived somatic TSC1 missense mutations cause loss of ... of constructs of wild-type TSC1 and the M224R variant, the latter showed lower levels ...
    www.ncbi.nlm.nih.gov/pmc/articles/PMC2427143/?tool=pubmed
  • Bladder tumour derived somatic TSC1 missense mutations cause ...
    mutations of TSC1 have been identified in 14.5% of tumours. ... transfections of constructs of wildtype TSC1 and the M224R variant, the latter ...
    hmg.oxfordjournals.org/cgi/reprint/ddn098v1.pdf
  • Bladder tumour-derived somatic TSC1 missense mutations cause ...
    TSC1 on chromosome 9q34 encodes hamartin (2) and TSC2 on chromosome 16p13.3 encodes ... constructs of wild-type TSC1 and the M224R variant, the latter showed ...
    hmg.oxfordjournals.org/cgi/content/full/17/13/2006
  • Supplementary Table 2 (doc 52K)
    ... TSC1 nucleotide changes on TSC1 mRNA splicing and TSC1 function, ... p.M224R. no. yes. pathogenic mutation. yes. no. c.737G>A. 8. p.R246K. predicted. no. probable ...
    www.nature.com/ejhg/journal/v17/n3/extref/ejhg2008170x2.doc
  • Biochemical characterisation of TSC1 and TSC2 variants ...
    2. Derivation of 12 unclassified TSC1 variants: 3 classified as ... 1. Application of functional assays to determine whether specific TSC1 and TSC2 ...
    dtic.mil/...?AD=ADA509747&Location=U2&doc=GetTRDoc.pdf
  • OMIM: 605284
    Potter et al. (2001) also showed that the Tsc1 protein binds to Drosophila Tsc2 in vitro. ... transversion in the TSC1 gene, resulting in a met224-to-arg (M224R) substitution. ...
    www.genome.jp/dbget-bin/www_bget?omim+605284
  • Bladder tumour-derived somatic TSC1 missense mutations cause ...
    Bladder tumour-derived somatic TSC1 missense mutations cause loss of ... of constructs of wild-type TSC1 and the M224R variant, the latter showed lower levels ...
    ukpmc.ac.uk/articlerender.cgi?artid=1553951&...&id=DDN098F4
  • 3 3
    TSC1 and TSC2 mutations and the neurological and cognitive phenotype in 58 patients with ... (L916R) and TSC1 892T>G (M224R)) was confi rmed by functional analysis ...
    igitur-archive.library.uu.nl/dissertations/.../c3.pdf
  • Identifi cation of epileptogenic tubers in patients with ...
    TSC1 and TSC2 mutations and the neurological and cognitive phenotype in 58 patients with ... (L916R) and TSC1 892T>G (M224R)) was confi rmed by functional analysis ...
    igitur-archive.library.uu.nl/dissertations/.../full.pdf

Other in silico analyses
 

  • NBLOSUM100 score = 4
  • GET-Evidence autoscore = 6

Edit history
 

Gene search

"GENE" or "GENE A123C":

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