Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000990176 | SCV001141024 | pathogenic | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV001664595 | SCV001470793 | likely pathogenic | not provided | 2019-09-03 | criteria provided, single submitter | clinical testing | The NOTCH3 c.3043T>C; p.Cys1015Arg variant is reported in the literature in multiple individuals affected with CADASIL (Oberstein 1999, Rutten 2016). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 1015 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. This variant lies within an EGF-like repeat domain, and pathogenic variants resulting in the gain or loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure (Dichgans 2000, Joutel 1997, Rutten 2016). Additionally, another variant at this codon (c.3043T>A; p.Cys1015Ser) has been reported in individuals with CADASIL (Zhu 2015). Based on available information, this variant is considered to be likely pathogenic. References: Dichgans M et al. Small in-frame deletions and missense mutations in CADASIL: 3D models predict misfolding of Notch3 EGF-like repeat domains. Eur J Hum Genet. 2000 Apr;8(4):280-5. Joutel A et al. Strong clustering and stereotyped nature of Notch3 mutations in CADASIL patients. Lancet. 1997 Nov 22;350(9090):1511-5. Oberstein SA et al. Diagnostic Notch3 sequence analysis in CADASIL: three new mutations in Dutch patients. Dutch CADASIL Research Group. Neurology. 1999 Jun 10;52(9):1913-5. Rutten J et al. Therapeutic NOTCH3 cysteine correction in CADASIL using exon skipping: in vitro proof of concept. Brain. 2016 Apr;139(Pt 4):1123-35. Rutten JW et al. Archetypal NOTCH3 mutations frequent in public exome: implications for CADASIL. Ann Clin Transl Neurol. 2016 Sep 28;3(11):844-853. Zhu Y et al. Two novel mutations in NOTCH3 gene causes cerebral autosomal dominant arteriopathy with subcritical infarct and leucoencephalopathy in two Chinese families. Int J Clin Exp Pathol. 2015 Feb 1;8(2):1321-7. |
| Athena Diagnostics Inc | RCV001664595 | SCV001879598 | pathogenic | not provided | 2022-03-04 | 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. 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. |
| DASA | RCV000990176 | SCV002061279 | pathogenic | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2022-01-05 | criteria provided, single submitter | clinical testing | The c.3043T>C;p.(Cys1015Arg) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 803539; PMID: 15995828; 12810003; 12821764; 12146805; 11571335) - PS4. Same amino acid change as a previously established pathogenic variant regardless of nucleotide change(PMID: 25973016) - PS1 This variant is not present in population databases (rs1599382214, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Pathogenic missense variant in this residue have been reported (PMID: 25973016) - PM5. Missense variant in NOTCH3 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. |
| Invitae | RCV001664595 | SCV002307175 | pathogenic | not provided | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1015 of the NOTCH3 protein (p.Cys1015Arg). 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 and lateral meningocele syndrome (PMID: 10371548; Invitae). ClinVar contains an entry for this variant (Variation ID: 803539). 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%. This variant disrupts the p.Cys1015 amino acid residue in NOTCH3. Other variant(s) that disrupt this residue have been observed in individuals with NOTCH3-related conditions (PMID: 25973016), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. |
| Clinical Genetics Laboratory, |
RCV000990176 | SCV003932628 | likely pathogenic | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2023-06-16 | criteria provided, single submitter | clinical testing | ACMG criteria used: PS4, PM2, PP3 |