Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004786281 | SCV005398523 | likely pathogenic | Autosomal dominant optic atrophy classic form | 2022-06-24 | 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 OPA1-related disease (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and mutations in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants clustered within the GTPase domain generally develop an optic atrophy syndrome. Lastly, biallelic variants have been associated with early onset Behr syndrome (PMID: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to valine. (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 uninformative conservation. (I) 0600 - Variant is located in the annotated GPTase domain (PMID: 20157015). (I) 0704 - An inframe deletion variant comparable to the missense variant identified in this case has limited previous evidence for pathogenicity. This variant, p.(Ile487del), has been reported in a single individual with dominant optic atrophy (PMID: 11440988). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been observed in an unrelated family with mitochondrial disease, chronic progressive external ophthalmoplegia (CPEO) and/or syndromic optic atrophy (PMID: 19029523; 20157015; 24086434). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant segregated with disease in a single family, however more meioses are required for pathogenicity to be established (PMID: 19029523; 20157015). (I) 1010 - Functional evidence for this variant is inconclusive. Functional analysis of patient fibroblasts did not demonstrate an effect on mitochondrial morphology when compared to controls (PMID: 34014035). (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| OMIM | RCV000023414 | SCV000044705 | pathogenic | Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy | 2008-11-25 | no assertion criteria provided | literature only | |
| Wellcome Centre for Mitochondrial Research, |
RCV000508763 | SCV000575921 | pathogenic | Mitochondrial disease | 2017-04-07 | no assertion criteria provided | clinical testing |