ClinVar Miner

Submissions for variant NM_015046.7(SETX):c.5949+5G>A (rs374656811)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000713224 SCV000680582 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing The c.5949+5G>A variant in the SETX gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is predicted to damage the splice donor site in intron 14, which may cause abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. The c.5949+5G>A variant is observed in 165/126,706 (0.13%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). We interpret c.5949+5G>A as a variant of uncertain significance.
Invitae RCV000644836 SCV000766551 uncertain significance Amyotrophic lateral sclerosis type 4; Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2019-09-21 criteria provided, single submitter clinical testing This sequence change falls in intron 14 of the SETX gene. It does not directly change the encoded amino acid sequence of the SETX protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs374656811, ExAC 0.2%). This variant has not been reported in the literature in individuals with SETX-related disease. ClinVar contains an entry for this variant (Variation ID: 488730). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Athena Diagnostics Inc RCV000713224 SCV000843810 likely benign not provided 2019-07-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001165667 SCV001327884 likely benign Amyotrophic lateral sclerosis type 4 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Clinical Services Laboratory,Illumina RCV001169651 SCV001332405 uncertain significance Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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