NOTCH2 P227H - GET-Evidence


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(NOTCH2 Pro227His)

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Edited in this revision:

Short summary

Probably benign. Predicted to be damaging by Polyphen 2 and other damaging variants cause Alagille syndrome, but this variant is not rare enough and has been seen in a healthy PGP participant.

Variant evidence
Computational -1

Polyphen 2 predicts damaging effect

Functional -
Case/Control 5

Present in a healthy PGP participant, allele frequency contradicts severe pathogenic effect

See unpublished research (below).

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

This variant is predicted to be damaging by Polyphen 2, but has been seen heterozygously in 2 out of 23 PGP + public genomes. Other variants in NOTCH2 are reported to cause Alagille syndrome (1 in 70,000 prevalence) in a dominant manner. The presence of this gene in a healthy PGP participant, and was seen in 2 out of 46 random PGP + public alleles, contradicting this variant as having a significant high penetrance pathogenic effect, and so we tentatively evaluate it as benign.

Even if a hypothetical pathogenic variant had only had moderate penetrance for causing Alagille syndrome (1%) and were responsible for 50% of cases, such a variant would have a frequency of .07% and the chances of seeing it twice in 46 random alleles would be p=0.00052.

Allele frequency

  • T @ chr1:120539691: 0.0% (2/10758) in EVS
  • T @ chr1:120341213: 4.3% (2/46) in GET-Evidence
  • Frequency shown in summary reports: 0.0% (2/10758)





GS19703 - var-GS19703-1100-36-ASM
het T @ chr1:120341214


Other external references

  • rs3899528
  • Score: 0.93 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 5
  • GET-Evidence autoscore = 4

Edit history

Gene search

"GENE" or "GENE A123C":

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