ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.4756_4760del (p.Asn1586fs)

dbSNP: rs765361868
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001568302 SCV001792145 pathogenic not provided 2021-12-28 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation, as the last 2994 amino acids are replaced with 2 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 30460542, 26153042, 27871429)
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001847304 SCV002105046 pathogenic Hereditary spastic paraplegia 2017-07-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001866008 SCV002212925 pathogenic Spastic paraplegia 2023-11-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn1586Tyrfs*3) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2994 amino acid(s) of the SACS protein. This variant is present in population databases (rs765361868, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with clinical features of SACS-related conditions (PMID: 27871429, 30460542). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1202576). 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.
Natera, Inc. RCV001832778 SCV002086270 pathogenic Charlevoix-Saguenay spastic ataxia 2020-05-19 no assertion criteria provided clinical testing
Solve-RD Consortium RCV001832778 SCV005200048 likely pathogenic Charlevoix-Saguenay spastic ataxia 2022-06-01 no assertion criteria provided provider interpretation Variant confirmed as disease-causing by referring clinical team

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