ClinVar Miner

Submissions for variant NM_018319.4(TDP1):c.1478A>G (p.His493Arg)

gnomAD frequency: 0.00002  dbSNP: rs119467003
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Baylor Genetics RCV000003593 SCV001524500 pathogenic Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 2019-11-06 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx RCV003128568 SCV003805616 pathogenic not provided 2022-08-23 criteria provided, single submitter clinical testing Published functional studies demonstrate that this variant creates a TDP1-DNA complex that results in reduced protein activity and altered protein function (Interthal et al., 2005a, Interthal et al. 2005b, Hirano et al. 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21463258, 21246735, 21167187, 22536944, 19883083, 22788692, 25024006, 25111769, 31723605, 24856239, 26601161, 17948061, 19139070, 22214184, 22522093, 23626666, 25841101, 29898404, 16141202, 19211312, 19476377, 21677033, 22155078, 24637157, 16935573, 19139134, 20687496, 20097655, 33425909, 15744309, 24236237, 31429931, 12244316, 31182267, 15920477)
Johns Hopkins Genomics, Johns Hopkins University RCV000003593 SCV003927253 pathogenic Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 2023-04-20 criteria provided, single submitter clinical testing This TDP1 variant (rs119467003) is absent from a large population dataset and has been reported in ClinVar. The histidine residue at this position is strongly conserved across the vertebrate species assessed. This amino acid substitution (p.His493Arg) changes a key active site residue that serves as a proton donor/acceptor. Functional studies demonstrate that this variant creates a TDP1-DNA covalent intermediate that results in reduced protein activity and altered protein function. This same variant has been detected in a homozygous state in three independent families with SCAN1. We consider c.1478A>G (p.His493Arg) to be pathogenic for autosomal recessive spinocerebellar ataxia with axonal neuropathy-1 (SCAN1).
OMIM RCV000003593 SCV000023751 pathogenic Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1 2002-10-01 no assertion criteria provided literature only

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