ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.5203G>A (p.Val1735Ile)

gnomAD frequency: 0.00001  dbSNP: rs752646721
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498384 SCV000590661 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the SETX gene. The V1735I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V1735I variant is observed in 2/66208 (0.003%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V1735I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV001851384 SCV002132700 uncertain significance Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2021-10-21 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 1735 of the SETX protein (p.Val1735Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs752646721, ExAC 0.003%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt SETX protein function. This variant has not been reported in the literature in individuals with SETX-related conditions. ClinVar contains an entry for this variant (Variation ID: 432889).
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002252142 SCV002523643 uncertain significance See cases 2020-04-09 criteria provided, single submitter clinical testing ACMG classification criteria: PM2, BP4
Genome-Nilou Lab RCV003233653 SCV003931343 uncertain significance Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2023-02-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV003233654 SCV003931345 uncertain significance Amyotrophic lateral sclerosis type 4 2023-02-08 criteria provided, single submitter clinical testing

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