ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.1166T>C (p.Leu389Ser) (rs29001584)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000724322 SCV000225032 pathogenic not provided 2014-09-30 criteria provided, single submitter clinical testing
Invitae RCV000644828 SCV000766543 pathogenic Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2017-08-16 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 389 of the SETX protein (p.Leu389Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with autosomal dominant juvenile ALS4 in several families (PMID: 15106121, 22088787) and has also been reported in an additional affected individual (PMID: 21438761). ClinVar contains an entry for this variant (Variation ID: 2289). Experimental studies have shown that this missense change does not affect senataxin interaction with exosome subunits or affect neuronal differentiation when overexpressed in hippocampal neurons (PMID: 24105744, 21576111). However, additional studies showed that senataxin protein carrying this variant does interact with protein targets that wild type protein does not interact with, which may suggest a possible pathogenic mechanism that has yet to be determined (PMID: 24244371). In summary, this is a rare missense change that interacts with abnormal target proteins and has been reported in multiple affected families. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000002379 SCV000022537 pathogenic Amyotrophic lateral sclerosis type 4 2004-06-01 no assertion criteria provided literature only
Inherited Neuropathy Consortium RCV000789615 SCV000928980 uncertain significance Distal spinal muscular atrophy no assertion criteria provided literature only

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