Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Athena Diagnostics Inc | RCV000518794 | SCV000614288 | pathogenic | not provided | 2021-02-03 | criteria provided, single submitter | clinical testing | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. In some published literature, this variant is referred to as c.428G>T. 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, |
RCV000518794 | SCV002049481 | pathogenic | not provided | 2020-12-10 | criteria provided, single submitter | clinical testing | The NOTCH3 c.350G>T; p.Cys117Phe variant (rs773539041), also published as c.428G>T, is reported in the literature in multiple individuals affected with CADASIL (Dichgans 1999, Matsushima 2017, Opherk 2004). This variant is reported in ClinVar (Variation ID: 447838). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. Additionally, other amino acid substitutions at this codon (p.Cys117Trp, p.Cys117Tyr, p.Cys117Arg, p.Cys117Ser) have been reported in individuals with CADASIL and are considered pathogenic (Ampuero 2009, Chen 2017, Spinicci 2013, Qin 2019). The cysteine at codon 117 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.974). 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.Cys117Phe variant is consistent with the predominant mechanism of disease in NOTCH3. Based on available information, this variant is considered to be pathogenic. References: Ampuero I et al. On the diagnosis of CADASIL. J Alzheimers Dis. 2009;17(4):787-94. 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. doi: 10.1111/cns.12719. Epub 2017 Jul 14. Erratum in: CNS Neurosci Ther. 2018 Dec;24(12):1312-1315. Dichgans M et al. Quantitative MRI in CADASIL: correlation with disability and cognitive performance. Neurology. 1999 Apr 22;52(7):1361-7. Matsushima T et al. Genotype-phenotype correlations of cysteine replacement in CADASIL. Neurobiol Aging. 2017 Feb;50:169.e7-169.e14. Opherk C et al. Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain. 2004 Nov;127(Pt 11):2533-9. doi: 10.1093/brain/awh282. Epub 2004 Sep 13. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. Spinicci G et al. Unusual clinical presentations in subjects carrying novel NOTCH3 gene mutations. J Stroke Cerebrovasc Dis. 2013 May;22(4):539-44. doi: 10.1016/j.jstrokecerebrovasdis.2013.02.002. Epub 2013 Mar 1. Qin W et al. Clinical Features of 4 Novel NOTCH3 Mutations of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy in China. Med Sci Monit Basic Res. 2019 Sep 26;25:199-209. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003317251 | SCV004020614 | pathogenic | NOTCH3-Related Disorders | 2023-06-29 | criteria provided, single submitter | clinical testing | Variant summary: NOTCH3 c.350G>T (p.Cys117Phe) results in a non-conservative amino acid change located in the EGF-like domain (IPR000742) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 226602 control chromosomes (gnomAD). c.350G>T has been reported in the literature in multiple individuals affected with cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) (e.g. Opherk_2004, Matsushima_2017, Wang_2011). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, other variants affecting the same amino acid (i.e. C117Y, C117W, C117R) have been reported in individuals with CADASIL/NOTCH3-related disorders, suggesting Cys117 is important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 10227618, 27890607, 15364702, 20935329). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |