ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.8844del (p.Ile2949fs) (rs281865117)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000338359 SCV000329911 pathogenic not provided 2016-08-31 criteria provided, single submitter clinical testing The c.8844delT pathogenic variant in the SACS gene has been reported previously in association with autosomalrecessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and is a founder mutation in the French Canadianpopulation (Engert et al., 2000; Thiffault et al., 2013; Duquette et al., 2013). The c.8844delT variant causes aframeshift starting with codon Isoleucine 2949, changes this amino acid to a Phenylalanine residue, and creates apremature Stop codon at position 4 of the new reading frame, denoted p.Ile2949PhefsX4. This variant is predicted tocause loss of normal protein function through protein truncation. The c.8844delT variant was not observed inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. We interpret c.8844delT as a pathogenicvariant.
Invitae RCV000460039 SCV000552973 pathogenic Spastic paraplegia 2018-10-09 criteria provided, single submitter clinical testing This sequence change deletes 1 nucleotide from exon 10 of the SACS mRNA (c.8844delT), causing a frameshift at codon 2949. This creates a premature translational stop signal in the last exon of the SACS mRNA (p.Ile2949Phefs*4). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1631 amino acids (~36%) of the SACS protein. This variant is clearly defined as an autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causative allele (PMID: 10655055, 11788093). It is a founder mutation in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. This variant is also known as g.6594delT in the literature. ClinVar contains an entry for this variant (Variation ID: 5512). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000005847 SCV000918180 pathogenic Spastic ataxia Charlevoix-Saguenay type 2017-10-16 criteria provided, single submitter clinical testing Variant summary: The SACS c.8844delT (p.Ile2949PhefsX4) variant results in a premature termination codon, predicted to cause a truncated or absent SACS protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The lack of the of sacsin protein was confirmed by Western blott performed on immortalized lymphoblasts extracted from homozygous carriers. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.11374C>T/p.Arg3792X). This variant was found in 17/276618 control chromosomes at a frequency of 0.0000615, which does not exceed the estimated maximal expected allele frequency of a pathogenic SACS variant (0.0079057). This variant appears to be a founder mutation in French-Canadian ARSACS patients (Thiffaul_2013). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000005847 SCV000026029 pathogenic Spastic ataxia Charlevoix-Saguenay type 2004-01-13 no assertion criteria provided literature only
GeneReviews RCV000005847 SCV000054639 pathologic Spastic ataxia Charlevoix-Saguenay type 2012-10-11 no assertion criteria provided curation Converted during submission to Pathogenic.
Counsyl RCV000005847 SCV000678179 pathogenic Spastic ataxia Charlevoix-Saguenay type 2017-06-02 no assertion criteria provided clinical testing

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