Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001127906 | SCV001287264 | uncertain significance | 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, 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. |
| Victorian Clinical Genetics Services, |
RCV001127906 | SCV002768554 | uncertain significance | Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 | 2020-07-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as 3B-VUS. Following criteria are met: 0103 - Gain of function is a known mechanism of disease in this gene and are associated with lateral meningocele syndrome. On the other hand, loss-of-function and dominant-negative are suspected mechanisms for cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (PMID: 25914166, 24844136, 30355220). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Pathogenic variants in EGFr domains 7-34 have a much higher population frequency and likely predispose to a milder small-vessel disease that may even be non-penetrant (PMID: 27844030, 30032161). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes. (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated EGF-like domain (DECIPHER, PDB, NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as a variant of uncertain significance (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |