ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.10466_10467del (p.Ser3489fs)

dbSNP: rs786204416
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000168999 SCV000220137 likely pathogenic Charlevoix-Saguenay spastic ataxia 2014-03-06 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168999 SCV001983640 likely pathogenic Charlevoix-Saguenay spastic ataxia 2021-09-18 criteria provided, single submitter clinical testing Variant summary: SACS c.10466_10467delCT (p.Ser3489LeufsX2) 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 was absent in 245712 control chromosomes. c.10466_10467delCT has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and has been subsequently cited by others (example Desserre_2011, Criscuolo_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000168999 SCV004209932 pathogenic Charlevoix-Saguenay spastic ataxia 2023-08-16 criteria provided, single submitter clinical testing
Invitae RCV003588582 SCV004295461 pathogenic Spastic paraplegia 2023-05-13 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SACS protein in which other variant(s) (p.Asn4549Asp) have been determined to be pathogenic (PMID: 15156359, 21507954). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 188710). This premature translational stop signal has been observed in individual(s) with SACS-related conditions (PMID: 21597885). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser3489Leufs*2) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1091 amino acid(s) of the SACS protein.

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