NOTCH3 P496L - GET-Evidence



(NOTCH3 Pro496Leu)

Short summary

Presumed benign, seen in two healthy PGP participants.

Variant evidence
Computational -1
Functional -
Case/Control 4

Presence in two healthy PGP participants strongly contradicts a severe pathogenic effect for this variant.

Familial -
Clinical importance
Severity -
Treatability -
Penetrance -


Low clinical importance, Uncertain benign

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

Inheritance pattern


Summary of published research, and additional commentary

Although Polyphen 2 predicts a damaging effect and this gene has clinical testing, the associated disease — CADASIL — has a dominant inheritance with a severe effect contradicted by the presence of this variant in two PGP participants who do not report this phenotype. In addition, substitution mutations causing CADASIL tend to associated with cysteine, although there are reports of cysteine-sparing mutations.

Genetests (Oberstein, Boon, and Dichgans. July 2003) reports “No other phenotype is known to be caused by mutations in the NOTCH3 gene.”

Allele frequency

  • A @ chr19:15299051: 1.6% (168/10752) in EVS
  • A @ chr19:15160050: 2.3% (3/128) in GET-Evidence
  • Frequency shown in summary reports: 1.6% (168/10752)



hu04FD18 - CGI sample GS00253-DNA_F01_200_37
het A @ chr19:15299051


hu0E64A1 - CGI sample GS01173-DNA_B02 from PGP sample 94378523
het A @ chr19:15299051


hu34D5B9 - CGI sample GS01173-DNA_C07 from PGP sample 92161424
het A @ chr19:15299051


huBEDA0B - CGI sample GS00253-DNA_C01_200_37
het A @ chr19:15299051


GS20502 - var-GS20502-1100-36-ASM
het A @ chr19:15160051


Other external references

  • rs11670799
  • Score: 0.993 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 7
  • GET-Evidence autoscore = 4

Edit history

Gene search

"GENE" or "GENE A123C":

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