Submissions for variant NM_130837.3(OPA1):c.1681+1G>T

dbSNP: rs886041318

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000300504	SCV000329707	pathogenic	not provided	2016-05-05	criteria provided, single submitter	clinical testing	The c.1516+1G>T pathogenic variant in the OPA1 gene has been reported previously in a family with autosomal dominant optic atrophy (Toomes et al., 2001). This splice site variant destroys the canonical splice donor site in intron 1. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.1516+1G>T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Splice site variants in the same position (c.1516+1G>C and c.1516+1G>A) have been reported in association with autosomal dominant optic atrophy (Schimpf et al., 2008; Santarelli et al., 2015), supporting the importance of this splice site. We interpret c.1516+1G>T as a pathogenic variant.
CeGaT Center for Human Genetics Tuebingen	RCV000300504	SCV001500771	pathogenic	not provided	2020-08-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000300504	SCV001905666	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786647	SCV005398025	pathogenic	Autosomal dominant optic atrophy classic form	2024-09-21	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with OPA1-related conditions (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 are clustered within the GTPase domain, generally develop optic atrophy plus syndrome. Lastly, biallelic variants have been associated with early onset Behr syndrome (PMIDs: 31500643, 28494813, 25012220, 30165240). (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 17306754). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0702 - Other splice variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Splice site variants in the same position (c.1681+1G>A and c.1681+1G>C) have been reported in individuals with autosomal dominant optic atrophy (ClinVar, PMIDs: 34242285, 25564500, 17722006). Additionally, a non-canonical splice variant (c.1681+3A>G) has also been reported in an individual with autosomal dominant optic atrophy, and functional analysis shows exon skipping and reduced mRNA abundance (PMID: 34242285). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least five individuals with autosomal dominant optic atrophy (ClinVar, PMID: 11440989, 35273349, 20484224). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV004542968	SCV004797944	pathogenic	OPA1-related disorder	2024-01-24	no assertion criteria provided	clinical testing	The OPA1 c.1681+1G>T variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also known as c.1516+1G>T in an alternate transcript (NM_015560), has been reported in a family with autosomal dominant optic atrophy and in additional unrelated individuals with autosomal dominant optic atrophy (Table 1, Toomes et al. 2001. PubMed ID: 11440989; Table 2, Yu-Wai-Man et al. 2011. PubMed ID: 20952381). This variant has not been reported in a large population database, indicating this variant is rare. Other variants affecting the same splice donor site, c.1681+1G>C and c.1681+1G>A, have been reported in individuals with autosomal dominant optic atrophy (reported as 1516+1G>C and 1516+1G>A, Table 1, Schimpf et al 2008. PubMed ID: 17722006; Table 2, Weisschuh N et al 2021. PubMed ID: 34242285). Taken together, we interpret this variant as pathogenic.