ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.5125C>T (p.Gln1709Ter) (rs1057517311)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412006 SCV000487079 pathogenic Charlevoix-Saguenay spastic ataxia 2016-10-04 criteria provided, single submitter clinical testing
Invitae RCV001224413 SCV001396605 pathogenic Spastic paraplegia 2020-03-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SACS gene (p.Gln1709*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2871 amino acids of the SACS protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) (PMID: 18465152, 23497566). ClinVar contains an entry for this variant (Variation ID: 371484). This variant disrupts the C-terminus of the SACS protein. Other variant(s) that disrupt this region (p.Arg3903*) have been determined to be pathogenic (PMID: 9892370, 21745802). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000412006 SCV001737756 pathogenic Charlevoix-Saguenay spastic ataxia 2021-05-31 criteria provided, single submitter clinical testing Variant summary: SACS c.5125C>T (p.Gln1709X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 247518 control chromosomes. c.5125C>T has been reported in the literature in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (example, Vermeer_2008, Synofzik_2013). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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