Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788353 | SCV005400125 | likely pathogenic | Cerebellar atrophy, visual impairment, and psychomotor retardation; | 2023-12-21 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with cerebellar atrophy, visual impairment, and psychomotor retardation (MIM#616875). (I) 0108 - This gene is associated with both recessive and dominant disease. There have been emerging reports for monoallelic inheritance (PMIDs: 26942288, 35234901). (I) 0115 - Variants in this gene are known to have variable expressivity. Some features are different among probands, and the severity may also vary (PMIDs: 26942288, 35234901). (I) 0200 - Variant is predicted to result in a missense amino acid change glycine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A change to arginine has been reported de novo in an individual with global developmental delay, hypotonia, scoliosis, and cerebellar atrophy (PMID: 26942288). In vitro studies in knockdown Xenopus have showed this variant was able to rescue phenotype, but to a lesser extent compared to wild-type, and authors suggest this may be a mild allele (PMID: 31904590). (SP) 0807 - This variant has no previous evidence of pathogenicity. (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) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis performed by an external laboratory). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |