Submissions for variant NM_000435.3(NOTCH3):c.521G>A (p.Cys174Tyr)

dbSNP: rs1555729486

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000517015	SCV000614309	pathogenic	not provided	2019-06-14	criteria provided, single submitter	clinical testing	The variant disrupts a cysteine residue in an EGF-like repeat domain, which are important for the structure of this protein. Therefore it is expected to severely affect the function of the protein. Found in at least one symptomatic patient, and not found in general population data.
CeGaT Center for Human Genetics Tuebingen	RCV000517015	SCV001249855	pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000517015	SCV001446907	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Invitae	RCV000517015	SCV001592430	pathogenic	not provided	2022-07-12	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys174 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 12810003), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NOTCH3 protein function. ClinVar contains an entry for this variant (Variation ID: 447854). This missense change has been observed in individuals with CADASIL (PMID: 10227618, 15364702, 16009764, 19180562, 22664156; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 174 of the NOTCH3 protein (p.Cys174Tyr).
PreventionGenetics, part of Exact Sciences	RCV003409735	SCV004111337	pathogenic	NOTCH3-related condition	2022-12-15	criteria provided, single submitter	clinical testing	The NOTCH3 c.521G>A variant is predicted to result in the amino acid substitution p.Cys174Tyr. This variant has been reported in individuals affected with CADASIL (Dichgans et al. 1999. PubMed ID: 10227618). Alternate missense changes affecting the same amino acid position have also been reported in patients with CADASIL (Human Gene Mutation Database; Testi et al. 2012. PubMed ID: 22664156; 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 four. 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.