Submissions for variant NM_000435.3(NOTCH3):c.1258G>T (p.Gly420Cys)

dbSNP: rs1323608032

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000517350	SCV000614215	pathogenic	not provided	2023-03-20	criteria provided, single submitter	clinical testing	This variant has been identified in at least one individual with clinical features of 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).
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761306	SCV000891283	likely pathogenic	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1	2018-02-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000517350	SCV001472640	pathogenic	not provided	2022-06-20	criteria provided, single submitter	clinical testing	The NOTCH3 c.1258G>T; p.Gly420Cys variant (rs1323608032) is reported in the literature in multiple individuals affected with CADASIL (Joutel 2001, Mehta 2013, Sathe 2009). This variant is in ClinVar (Variation ID: 447778), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 420 is highly conserved, and computational analyses (SIFT) predict that this variant is deleterious. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014), and thus the p.Gly420Cys variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be pathogenic. References: Joutel A et al. Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet. 2001 Dec 15;358(9298):2049-51. Mehta S et al. Spontaneous cerebellar hemorrhage associated with a novel Notch3 mutation. J Clin Neurosci. 2013 Jul;20(7):1034-6. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Sathe S et al. Acute confusional migraine may be a presenting feature of CADASIL. Headache. 2009 Apr;49(4):590-6.
Invitae	RCV000517350	SCV002149835	pathogenic	not provided	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 420 of the NOTCH3 protein (p.Gly420Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1 (PMID: 11755616, 19245392, 23623146, 34851492; Invitae). ClinVar contains an entry for this variant (Variation ID: 447778). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NOTCH3 protein function. For these reasons, this variant has been classified as Pathogenic.
GenomeConnect - CureCADASIL	RCV000761306	SCV001245245	not provided	Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 09-22-2010 by Lab or GTR ID 1012. GenomeConnect-CureCADASIL assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.