ClinVar Miner

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

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674417 SCV000799750 likely pathogenic Spastic ataxia Charlevoix-Saguenay type 2018-05-04 criteria provided, single submitter clinical testing
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.
Invitae RCV000706287 SCV000835327 pathogenic Spastic paraplegia 2018-05-30 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.

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