ClinVar Genomic variation as it relates to human health

Variant summary: SACS c.10906C>T (p.Arg3636X) results in a premature termination codon in the last exon, that is not expected to result in nonsense mediated decay (NMD), but is predicted to cause a large truncation of the encoded protein. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.11374C>T (p.Arg3792X)). The variant allele was found at a frequency of 1.2e-05 in 250508 control chromosomes (gnomAD). The variant, c.10906C>T, has been reported in the literature in multiple compound heterozygous- and a homozygous individual affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (Vermeer_2008, Walsh_2017, Sun_2019, Tsugawa_2015). These data indicate that the variant is likely to be 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 and laboratories classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic.

This sequence change creates a premature translational stop signal (p.Arg3636*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 944 amino acid(s) of the SACS protein. This variant is present in population databases (rs780247476, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with early-onset cerebellar ataxia (PMID: 18465152). ClinVar contains an entry for this variant (Variation ID: 212108). This variant disrupts a region of the SACS protein in which other variant(s) (p.Arg3903*) have been determined to be pathogenic (PMID: 19892370, 21745802). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

The c.10906C>T (p.R3636*) alteration, located in exon 10 (coding exon 9) of the SACS gene, consists of a C to T substitution at nucleotide position 10906. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 3636. This alteration occurs at the 3' terminus of the SACS gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 20% of the protein. However, premature stop codons are typically deleterious in nature and a pathogenic truncating mutation downstream has been reported (Vermeer, 2008). This alteration was reported in two brothers and another unrelated patient with autosomal recessive spastic ataxia of Charlevoix Saguenay. They were all found to be compound heterozygous for a second truncating alteration in SACS (Vermeer, 2008; Sun, 2019). Based on the available evidence, this alteration is classified as pathogenic.