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

dbSNP: rs947976672

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	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	RCV004527622	SCV004112750	pathogenic	NOTCH3-related disorder	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000517341	SCV005836959	likely pathogenic	not provided	2024-02-20	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 258 of the NOTCH3 protein (p.Tyr258Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or clinical features of this condition (PMID: 9388399, 12821764, 28710804, 32277177, 32555735; Invitae). This variant is also known as A851G. ClinVar contains an entry for this variant (Variation ID: 447873). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.