ClinVar Miner

Submissions for variant NM_004618.5(TOP3A):c.1723A>G (p.Met575Val)

gnomAD frequency: 0.00002  dbSNP: rs372121045
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Undiagnosed Diseases Network, NIH RCV000787955 SCV000926977 uncertain significance Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 5 2018-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV003362937 SCV004052988 pathogenic Inborn genetic diseases 2023-06-29 criteria provided, single submitter clinical testing The c.1723A>G (p.M575V) alteration is located in exon 15 (coding exon 15) of the TOP3A gene. This alteration results from a A to G substitution at nucleotide position 1723, causing the methionine (M) at amino acid position 575 to be replaced by a valine (V). Based on data from gnomAD, the G allele has an overall frequency of 0.002% (6/282702) total alleles studied. The highest observed frequency was 0.005% (1/19942) of East Asian alleles. This variant has been identified in trans with a TOP3A likely pathogenic/pathogenic variant in multiple individuals diagnosed with clinical features consistent with TOP3A-related mitochondrial disease (Erdinc, 2023). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, this variant is anticipated to disrupt the DNA-binding activity of the protein (Bocquet, 2014; Erdinc, 2023). Functional assays show impaired DNA binding and topoisomerase activity in vitro (Erdinc, 2023). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

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