Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788510 | SCV005398143 | likely pathogenic | Intellectual disability, autosomal dominant 9 | 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: 0103 - Dominant negative, loss of function and gain of function are known mechanisms of disease in this gene. Dominant negative effect has been shown to cause NESCAV syndrome (MIM#614255; OMIM). Both loss and gain of function mechanisms have been reported for variants causing spastic paraplegia (MIM#610357, MIM#610357) and hereditary sensory and autonomic neuropathy type 2 (HSAN2; MIM#614213) (PMID 31488895, 31455732). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. Genotype-phenotype correlation is currently unestablished. Missense variants tend to cluster within the kinesin motor domain and have been reported for both SPG30 and NESCAV syndrome. Only the correlation for HSAN2 (MIM#614213) is established with all patients except for one, carrying null variants outside the motor domain (PMID: 32737135). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to proline. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and very highly conserved with a moderate amino acid change. (I) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.(Gln671Glu)) has been reported once as a VUS (ClinVar). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported once as a VUS, in an individual with cerebral palsy, visual loss, gastrointestinal issues and clinical suspicion of mitochondrial disease (ClinVar, personal communication). (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). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |