ClinVar Miner

Submissions for variant NM_000435.3(NOTCH3):c.773A>G (p.Tyr258Cys)

dbSNP: rs947976672
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000517341 SCV000614335 pathogenic not provided 2022-11-16 criteria provided, single submitter clinical testing This variant has been identified in multiple unrelated individuals with CADASIL. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. Greater than 90% of NOTCH3 pathogenic variants associated with CADASIL involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain (PMID: 32457593, 20301673).
GeneDx RCV000517341 SCV003929725 likely pathogenic not provided 2022-11-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24844136, 35775048, 9388399, 32555735, 32277177)
PreventionGenetics, part of Exact Sciences RCV003403219 SCV004112750 pathogenic NOTCH3-related condition 2022-11-07 criteria provided, single submitter clinical testing The NOTCH3 c.773A>G variant is predicted to result in the amino acid substitution p.Tyr258Cys. This variant has been reported in individuals with CADASIL (Joutel et al. 1997. PubMed ID: 9388399; Mukai et al. 2020. PubMed ID: 32277177; Kim et al. 2020. PubMed ID: 32555735). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Most CADASIL causing variants in the NOTCH3 gene result in the gain or loss of one or more cysteine residues in the extracellular domain of the protein, as seen in this patient. This patient’s variant alters a cysteine residue and is located in the extracellular EGFr-like domain six. Pathogenic variants in EGFr domains 1-6 appear to be fully penetrant and are usually associated with the classical CADASIL phenotype. However, there is variability in disease severity. Pathogenic variants in EGFr domains 7-34 have a much higher population frequency, and can predispose to a milder small-vessel disease, possibly even displaying incomplete or at least very late onset complete penetrance (OMIM #125310; Rutten et al. 2016. PubMed ID: 27844030; Rutten et al. 2019. PubMed ID: 30032161). This variant is interpreted as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.