Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000336250 | SCV000410939 | likely benign | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2018-01-13 | criteria provided, single submitter | clinical testing | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. |
| ARUP Laboratories, |
RCV001812861 | SCV001472862 | uncertain significance | not provided | 2020-08-14 | criteria provided, single submitter | clinical testing | The NOTCH3 c.6611C>T; p.Pro2204Leu variant (rs371738874), to our knowledge, is not reported in the medical literature but is reported as likely benign in ClinVar (Variation ID: 328371). This variant is found in the general population with an overall allele frequency of 0.01% (17/177386 alleles) in the Genome Aggregation Database. The proline at codon 2204 is highly conserved, but computational analyses (SIFT: Damaging, PolyPhen-2: Benign) predict conflicting effects of this variant on protein structure/function. Most pathogenic NOTCH3 variants occur in exons 2-24 and either create or destroy a cysteine residue within an EGF-like domain (Rutten 2014). However, there are several amino acid substitutions not involving cysteine that may be disease-associated (Muino 2017). Although p.Pro2204Leu does not occur within this critical region or involve a cysteine residue, due to limited information at this time, its clinical significance is uncertain. REFERENCES Muino E et al. Systematic Review of Cysteine-Sparing NOTCH3 Missense Mutations in Patients with Clinical Suspicion of CADASIL. Int J Mol Sci. 2017 Sep 13;18(9). pii: E1964. Rutten JW et al. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014 Jun;14(5):593-603. |
| Invitae | RCV001812861 | SCV002393094 | likely benign | not provided | 2023-03-29 | criteria provided, single submitter | clinical testing | |
| Mayo Clinic Laboratories, |
RCV001812861 | SCV004224573 | uncertain significance | not provided | 2022-09-30 | criteria provided, single submitter | clinical testing | BS2 |