ClinVar Miner

Submissions for variant NM_025136.4(OPA3):c.313C>G (p.Gln105Glu)

dbSNP: rs80356525
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000814602 SCV000955015 pathogenic 3-Methylglutaconic aciduria type 3; Optic atrophy 3 2022-01-16 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 4241). This missense change has been observed in individuals with autosomal dominant optic atrophy and cataract (PMID: 15342707, 24136862, 25159689). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 105 of the OPA3 protein (p.Gln105Glu).
CeGaT Center for Human Genetics Tuebingen RCV001092423 SCV001248930 pathogenic not provided 2018-12-01 criteria provided, single submitter clinical testing
GeneDx RCV001092423 SCV002599603 pathogenic not provided 2022-05-02 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15342707, 18496845, 24749080, 22797356, 24136862, 25159689, 31119193)
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000004463 SCV003798453 pathogenic Optic atrophy 3 2023-02-07 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000004463 SCV005400002 pathogenic Optic atrophy 3 2021-05-06 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 3-methylglutaconic aciduria, type III (MIM#258501) (PMID: 31928268). The precise mechanism for missense is unknown, however it was suggested they could cause dominant Optic atrophy 3 with cataract (MIM#165300) through either dominant negative or gain of function mechanism (PMID: 31119193). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Intra- and interfamilial variability are reported (PMID: 25159689). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamine to glutamic acid. (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 coiled-coil domain (Uniprot). (I) 0701 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. A different variant in the same codon resulting in a change to an arginine has been reported as VUS (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This is the most frequent mutation reported in patients with dominant optical atrophy (ClinVar, PMID: 25159689, 31119193). (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 RCV000004463 SCV000024636 pathogenic Optic atrophy 3 2004-09-01 no assertion criteria provided literature only
GeneReviews RCV000004463 SCV000041513 not provided Optic atrophy 3 no assertion provided literature only

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