ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.8793del (p.Lys2931fs) (rs767871841)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519077 SCV000617740 likely pathogenic not provided 2018-11-09 criteria provided, single submitter clinical testing The c.8793delA variant in the SACS gene has been reported previously in two siblings with spastic ataxia who were homozygous for the c.8793delA variant (Hara et al., 2005). The c.8793delA variant causes a frameshift starting with codon Lysine 2931, changes this amino acid to a Asparagine residue, and creates a premature Stop codon at position 22 of the new reading frame, denoted p.Lys2931AsnfsX22. This variant is predicted to cause loss of normal protein function through protein truncation. The c.8793delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.8793delA as a likely pathogenic variant.
Counsyl RCV000674417 SCV000799750 likely pathogenic Charlevoix-Saguenay spastic ataxia 2018-05-04 criteria provided, single submitter clinical testing
Invitae RCV000706287 SCV000835327 pathogenic Spastic paraplegia 2019-05-20 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SACS gene (p.Lys2931Asnfs*22). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1649 amino acids (~36%) of the SACS protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with autosomal recessive spastic ataxia in a family (PMID: 15486997). This variant is also known as 6543delA in the literature. ClinVar contains an entry for this variant (Variation ID: 449517). A different truncation (p.Arg3636*) that lies downstream of this variant has been determined to be pathogenic (PMID: 18465152). This suggests that deletion of this region of the SACS protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc RCV000519077 SCV001145350 pathogenic not provided 2018-09-18 criteria provided, single submitter clinical testing The variant results in a shift of the reading frame, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674417 SCV001737737 pathogenic Charlevoix-Saguenay spastic ataxia 2021-06-11 criteria provided, single submitter clinical testing Variant summary: SACS c.8793delA (p.Lys2931AsnfsX22) 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 250652 control chromosomes. c.8793delA has been reported in the literature as a homozygous mutation in several individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay, including 2 affected siblings (e.g. Hara_2005, Shakya_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Human Genetics, Klinikum rechts der Isar RCV000674417 SCV001149910 pathogenic Charlevoix-Saguenay spastic ataxia 2018-04-06 no assertion criteria provided clinical testing

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