ClinVar Miner

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

dbSNP: rs29001584
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724322 SCV000225032 pathogenic not provided 2014-09-30 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000644828 SCV000766543 pathogenic Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2022-08-06 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 2289). For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SETX function (PMID: 21576111, 24105744, 24244371). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SETX protein function. This missense change has been observed in individuals with autosomal dominant juvenile amyotrophic lateral sclerosis (PMID: 15106121, 21438761, 22088787). 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 leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 389 of the SETX protein (p.Leu389Ser).
GeneDx RCV000724322 SCV001826566 pathogenic not provided 2023-03-02 criteria provided, single submitter clinical testing Published functional studies demonstrate increased promoter methylation and decreased gene transcription, by reducing R-loops and BAMBI expression, while increasing TGF-B signaling (Grunseich et al., 2018).; 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: 30528841, 32997296, 24244371, 24105744, 29395064, 29725819, 9497266, 10430837, 23129421, 22088787, 29916023, 28413711, 27796045, 31957062, 15106121, 21438761)
Genome-Nilou Lab RCV003233065 SCV003931559 pathogenic Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2023-02-08 criteria provided, single submitter clinical testing
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
Inherited Neuropathy Consortium Ii, University Of Miami RCV000002379 SCV004011924 uncertain significance Amyotrophic lateral sclerosis type 4 2016-01-06 no assertion criteria provided literature only

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