Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788506 | SCV005398133 | likely pathogenic | Optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy | 2021-05-06 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant which is in the same haplotype as the p.T376A 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 Behr syndrome (MIM#210000), optic atrophy 1 (MIM#165500) and optic atrophy syndrome (MIM#125250). (I) 0108 - This gene is associated with both recessive and dominant disease. Truncating variants and pathogenic variants in the C-terminal domain are associated with dominant optic atrophy. Individuals carrying missense variants that are clustered within the GTPase domain generally develop 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 and has been reported for optic atrophy 1 (MIM#165500) (PMID: 17306754). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (highest allele count: 4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated GTPase domain (PMID: 11855928). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0901 - This variant has strong evidence for segregation with disease. This variant, shown to be in cis with the p.T376A variant, has been reported to segregate in 51 family members with 100% penetrance (PMID: 17306754). (SP) 1010 - Functional evidence for this variant is inconclusive. Although Vanbergen et al (2011) demonstrated reduced OPA1 protein levels and impaired OXPHOS efficiency, their experiments were performed on combined total protein lysates from lymphoblastoid cell lines generated from multiple carriers of pathogenic variants, including a cell line carrying both p.I313E and p.T376A. Therefore, it is difficult to determine the specific functional consequence of our variant of interest (PMID: 21731710). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |