NOTCH3 P496L - GET-Evidence

Curation:
Currentness:

NOTCH3 P496L

(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 -
 

Impact

Low clinical importance, Uncertain benign

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

Inheritance pattern

unknown

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)

Publications
 

Genomes
 

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
 

    dbSNP
  • rs11670799
    www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi
    PolyPhen-2
  • 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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