Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics | RCV000517629 | SCV000614264 | pathogenic | not provided | 2022-05-11 | criteria provided, single submitter | clinical testing | This variant has been identified in at least one individual 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 pathogenic variants identified in NOTCH3 involve the gain or loss of a cysteine residue within the epidermal growth factor (EGF)-like repeat domain. |
| ARUP Laboratories, |
RCV000517629 | SCV002048046 | likely pathogenic | not provided | 2020-12-08 | criteria provided, single submitter | clinical testing | The NOTCH3 c.2951T>G; p.Phe984Cys variant (rs995523352) has been described in the literature in several individuals diagnosed with CADASIL (Abramycheva 2015, Chen 2017, Escary 2000). The variant is reported in the ClinVar database (Variation ID: 447818) and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The phenylalanine at codon 984 is located in exon 18, is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.762). Additionally, most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). Based on available information, this variant is considered to be likely pathogenic. References: Abramycheva N et al. New mutations in the Notch3 gene in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). J Neurol Sci. 2015 Feb 15;349(1-2):196-201. Chen S et al. Clinical features and mutation spectrum in Chinese patients with CADASIL: A multicenter retrospective study. CNS Neurosci Ther. 2017 Sep;23(9):707-716. Escary JL et al. Evaluation of DHPLC analysis in mutational scanning of Notch3, a gene with a high G-C content. Hum Mutat. 2000 Dec;16(6):518-26. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. |