NOTCH3 A1020P - GET-Evidence



(NOTCH3 Ala1020Pro)

Short summary

Probably nonpathogenic. Reported by Scheid et al. as possibly causing CADASIL in a dominant manner, but an immediate follow-up from Quattrone et al. disagreed with this hypothesis, pointing to the presence of the variant in their own controls and the high allele frequency for the variant seen in dbSNP data.

Variant evidence
Computational 2

Polyphen 2 predicts benign effect, BLOSUM100 score indicates Ala to Pro is not very disruptive.

Functional -
Case/Control 4

Dominant pathogenic effect is contradicted by the frequency of this allele in the population.

See 19528524.


Segregates in one family, but LOD is less than 1.

Clinical importance
Severity -
Treatability -
Penetrance -

Reported effect implied highly penetrant

See 18765654.



Low clinical importance, Likely benign

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

Inheritance pattern


Summary of published research, and additional commentary

1000 Genomes, if reliable as controls, makes this conclusion highly improbable.

Unpublished cases/controls case+ case– control+ control– p-value odds ratio
- - 42 184 - -


Total cases/controls case+ case– control+ control– p-value odds ratio
2 0 42 285 0.0175


Allele frequency

  • G @ chr19:15291576: 11.2% (1202/10748) in EVS
  • G @ chr19:15152575: 14.1% (18/128) in GET-Evidence
  • Frequency shown in summary reports: 11.2% (1202/10748)


Scheid R, Heinritz W, Leyhe T, Thal DR, Schober R, Strenge S, von Cramon DY, Froster UG. Cysteine-sparing notch3 mutations: cadasil or cadasil variants? Neurology. 2008 Sep 2;71(10):774-6. PubMed PMID: 18765654.

This variant segregated with disease in a proband containing three affected individuals (patient, mother, and maternal uncle, all heterozygous). One additional unrelated patient was also heterozygous. This variant was not seen in >100 genomes tested. While cysteine residues are usually involved in CADASIL, this residue is highly conserved and there is a mutation cluster around this site. The LOD score for this family is 0.9.

Cases/controls case+ case– control+ control– p-value odds ratio
2 0 0 101 0.0002


Quattrone A, Mazzei R. Cysteine-sparing notch3 mutations: cadasil or cadasil variants? Neurology. 2009 Jun 16;72(24):2135-6; author reply 2136. PubMed PMID: 19528524.

These authors reply to Scheid et al. and strongly disagree with the pathogenic hypothesis, pointing to the presence of this variant in their own controls and reported allele frequencies within dbSNP data.

Mitsuhashi Y, Horiuchi A, Miyamoto T, Kashima H, Suzuki A, Shiozawa T. Prognostic significance of Notch signalling molecules and their involvement in the invasiveness of endometrial carcinoma cells. Histopathology. 2012 Apr;60(5):826-37. doi: 10.1111/j.1365-2559.2011.04158.x. Epub 2012 Feb 20. PubMed PMID: 22348356.

Not relevant?



GS07357 - var-GS07357-1100-36-ASM
het G @ chr19:15152576


GS18502 - var-GS18502-1100-36-ASM
het G @ chr19:15152576


GS18508 - var-GS18508-1100-36-ASM
het G @ chr19:15152576


GS18517 - var-GS18517-1100-36-ASM
het G @ chr19:15152576


GS19017 - var-GS19017-1100-36-ASM
het G @ chr19:15152576


GS19025 - var-GS19025-1100-36-ASM
het G @ chr19:15152576


GS19026 - var-GS19026-1100-36-ASM
het G @ chr19:15152576


GS19129 - var-GS19129-1100-36-ASM
hom G @ chr19:15152576


GS19238 - var-GS19238-1100-36-ASM
hom G @ chr19:15152576


GS19239 - var-GS19239-1100-36-ASM
het G @ chr19:15152576


GS19240 - var-GS19240-1100-36-ASM
hom G @ chr19:15152576


GS19648 - var-GS19648-1100-36-ASM
hom G @ chr19:15152576


GS19701 - var-GS19701-1100-36-ASM
het G @ chr19:15152576


GS19703 - var-GS19703-1100-36-ASM
hom G @ chr19:15152576


GS19834 - var-GS19834-1100-36-ASM
het G @ chr19:15152576


Other external references

  • rs35769976
  • Score: 0.003 (benign)
    Web search results (7 hits -- see all)
  • Neurology -- Correspondence for Scheid et al., 71 (10) 774-776
    First, the A1020P is classified as SNP with the reference number ... presence of complex rearrangements in the NOTCH3 gene, it is not possible to exclude ...
  • OMIM: 600276
    Screening of 14 of the 29 NOTCH3 exons by SSCP revealed 11 conformational ... in the NOTCH3 gene, resulting in an ala1020-to-pro (A1020P) substitution in a ...
  • Poster Session
    Suggestive clinical features and NOTCH3 gene variants: CADASIL or CADASIL-like? ... the NOTCH3 gene in both sisters presented the following sequence variants: p.A1020P in ...

Other in silico analyses

  • NBLOSUM100 score = 2
  • GET-Evidence autoscore = 4

Edit history

Gene search

"GENE" or "GENE A123C":

Log in