ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.9508C>T (p.Arg3170Ter) (rs202199411)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000297710 SCV000329910 pathogenic not provided 2017-08-03 criteria provided, single submitter clinical testing The R3170X variant in the SACS gene has been reported previously in at least one individual with autosomal recessive spastic ataxia Charlevoix-Saguenay type who also harbors a frameshift variant in the SACS gene (Thiffault et al., 2013). This variant causes the loss of the last 1410 amino acid residues, which is predicted to cause loss of normal protein function through protein truncation. Protein truncating pathogenic variants downstream of this variant have been reported in the Human Gene Mutation Database in association with SACS-related disorders (Stenson et al., 2014), supporting the pathogenicity of more upstream truncating variants. The R3170X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Thus, we interpret R3170X as a pathogenic variant.
Athena Diagnostics Inc RCV000297710 SCV000843554 pathogenic not provided 2016-03-11 criteria provided, single submitter clinical testing
Invitae RCV001223182 SCV001395319 pathogenic Spastic paraplegia 2020-08-23 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the SACS gene (p.Arg3170*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1,410 amino acids of the SACS protein. This variant is present in population databases (rs202199411, ExAC 0.002%). This variant has been observed in an individual affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 23250129). ClinVar contains an entry for this variant (Variation ID: 280094). 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: 19892370, 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.
Counsyl RCV000411666 SCV000486037 likely pathogenic Charlevoix-Saguenay spastic ataxia 2016-04-05 no assertion criteria provided clinical testing

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