CST3

Inheritance Pattern: AD

Disease ID:MONDO:0007098

Submitter: ClinGen

*CST3* was first reported in relation to autosomal dominant Acys amyloidosis in 1987 (Jensson O et al., PMID:3673496). Acys amyloidosis is reported in Icelandic families who have amyloid deposition in cerebral and spinal arteries and arterioles that leads to recurrent hemorrhagic strokes, brain damage, and fatality. Only one missense variant has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in *CST3 *have been reported in individuals with the following disease entities: autosomal dominant, adult onset leukodystrophy without amyloid angiopathy and ACys. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found distinct differences in molecular mechanism and phenotypic variability between the disease assertions for *CST3*. One single missense variant is reported in Acys amyloidosis and only truncating variants are reported with adult-onset leukodystrophy. Neuropathologic studies do not show cerebral amyloid angiopathy or amyloid deposition in the adult-onset leukodystrophy cases. This is a defining feature of the Acys amyloidosis. Therefore, the following disease entities have been split: leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy (MONDO:0979226) and Acys amyloidosis (MONDO:0005620). The split curation for autosomal dominant leukodystrophy without amyloid angiopathy (MONDO:0979226) has been curated separately. Variants in this gene have been reported in at least 2 probands in 2 publications (PMID:1352269, 7482672). There is functional evidence that supports an upscoring of this variant (PMID:6886625, 8108423). Variants in this gene segregated with disease in 46 additional family members. This gene-disease relationship is supported by expression studies showing the protein expressed highly in the brain and a cell culture model showing the same variant protein aggregation seen in patients (PMID: 24309898, 10193512). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Neurovascular Gene Curation Expert Panel on the meeting date June 24, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0979226

Submitter: ClinGen

*CST3* was first reported in relation to autosomal dominant adult-onset leukodystrophy in 2024 (Bergner CG et al., PMID:38489591). The disease is characterized by adult onset of variable neurologic symptoms, including recurrent hemiplegic migraine, progressive motor abnormalities, and cognitive decline. Brain MRIs show changes involving the deep cerebral white matter, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles, and globus pallidus. Neuropathologic studies do not show cerebral amyloid angiopathy or amyloid deposition. Cystatin C levels in serum and cerebral spinal fluid are decreased as compared to controls. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found distinct differences in molecular mechanism and phenotypic variability between the disease assertions for *CST3*. One single missense variant is reported in Acys amyloidosis and only truncating variants are reported with adult-onset leukodystrophy. Neuropathologic studies do not show cerebral amyloid angiopathy or amyloid deposition in the adult-onset leukodystrophy cases. This is a defining feature of the Acys amyloidosis. Therefore, the following disease entities have been split: leukodystrophy, adult-onset, autosomal dominant, without amyloid angiopathy (MONDO:0979226) and Acys amyloidosis (MONDO:0005620). The split curation for autosomal dominant Acys amyloidosis (MONDO:0005620) has been curated separately. Six truncating variants (nonsense, frameshift deletion) that have been reported in nine probands in five publications (PMIDs:38489591, 38729262, 41033143, 39292282, 38965776) are included in this curation. There are pedigrees of affected families in the literature, but they do not have enough segregations to be scored, per the ClinGen Gene Curation SOP. There are more probands reported in the literature than scored here, but they carry variants that were already awarded points. All probands were downscored due to the end-truncating variants existing in either the last exon for the last 50bp of the penultimate exon. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by expression studies (PMID:24309898) that demonstrate that *CST3* is highly expressed in the brain, a relevant organ to this disease. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.This classification was approved by the ClinGen Neurovascular GCEP on the meeting date April 22, 2026 (SOP Version 12).

Inheritance Pattern: AD

Disease ID:MONDO:0007098

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0007098

Submitter: Orphanet