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genetics:variants:thr307ile [Retinoblastoma Wiki]
 

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p.Thr307Ile

  • c.920C>T
  • g.61788C>T

instances of observation

  • Patient 171 (To) uni, isol: Tumor and blood showed a non-germline heterozygous c.1853C>G (p.Ser618X) and non-germline heterozygous IVS8+1G>A (c.861+1G>A) in addition to heterozygous c.920C>T (p.Thr307Iso) (reported by Diane Rushlow, updated 01/2012)
  • Patient 836 (To) uni, isol: Hetero Thr307Iso in blood; no tumor available. Unaffected mother also carries this change (reported by Diane Rushlow)
  • Patient 4601 (E) het in blood of patient with isolated unilateral rb, inherited from unaffected mother, present in unaffected sister (reported by Dietmar Lohmann)
  • Patient 4822 (E) het in blood and tumor of patient with isolated unilateral rb, inherited from unaffected mother, transmitted to still unaffected child (reported by Dietmar Lohmann)
  • 1000GENOMES:low_coverage:NA12043 (M)
  • no ID (Man) unilateral patient who has this change in his blood. His mother, paternal uncle and cousin are all unaffected but carry the variant (reported Tracy Colclough)
  • :!: please add observations if possible
  • unilateral sporadic patient: two pathogenic non-germline mutations in tumour plus hetero Thr307I in tumour and blood. Unaffected father and 2.5 year old sib also carry this change (reported by Zerrin Onadim - 19.08.2014)
  • (Another patient(Fam 1858) was previously thought to be bilateral, with only heterozygous c.920C>T (p.Thr307Iso) identified in blood. Further information indicated that this patient ‘s symptoms most closely indicated bilateral manifestation of fever, and that very likely this patient did not have retinoblastoma.)

suggestion

  • testing for identity by descent
  • collecting data of the frequency of observation in bilateral rb pts compared to unilateral rb pts

—-



Classification of Pathogenicity

good evidence against pathogenicity

  • Observation in Patient 171 makes it more likely that the Thr307Iso is a bystander and not involved in the initiation of this patient’s tumor, the missense change is not effective as a first hit and the regular two obvious pathogenic mutations were needed to start the retinoblastoma. This is good evidence against pathogenicity (hereditary rb).
  • observed in a „normal control individual CEU“



Additional Info

Structural evidence
  • Thr307Ile The residue sits on an unstructured loop. We made this mutant and are looking at it. The mutant is stabile and reduces colony formation but we see a rather peculiar loss of function. There are “flat cells” forming when we express it in Saos2 but these are not spread out with ragged cell border, as one gets with wtRB-1, but circular with clearly smaller perimeter. I am not sure what to make of it at the moment but it came out like this in three independent experiments. We see the same phenotype also with E313G and K319R. E313 and K319R are positioned on the helix following on from the T307 containing loop but in the three dimensional structure are lie right next to T 307. So we think there is some functional surface but we don’t have a firm view what the function is that it confers. (Sibylle)
  • Thus, as far as biochemistry is concerned, there is a documentable loss of function. Whether this loss explains the cancer we cannot be sure.
 
genetics/variants/thr307ile.txt · Last modified: 2014/08/19 11:01 by zonadim
 
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