Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000387915 | SCV000410994 | uncertain significance | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2018-01-12 | 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. |
| ARUP Laboratories, |
RCV001002581 | SCV001160554 | uncertain significance | not specified | 2019-05-02 | criteria provided, single submitter | clinical testing | The NOTCH3 c.2329C>T; p.Pro777Ser variant (rs886054259), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 328406). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The proline at codon 777 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Most NOTCH3 pathogenic variants involve the loss or addition of a cysteine residue, although there are several amino acid substitutions not involving cysteine that may be disease-associated (Muino 2017). However, due to limited information, the clinical significance of the p.Pro777Ser variant is uncertain at this time. 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. |