ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.7504C>T (p.Arg2502Ter)

gnomAD frequency: 0.00002  dbSNP: rs281865118
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000005848 SCV000678155 pathogenic Charlevoix-Saguenay spastic ataxia 2015-09-03 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001268308 SCV001447139 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Medical Genetics Laboratory, Tarbiat Modares University RCV000005848 SCV001622769 pathogenic Charlevoix-Saguenay spastic ataxia 2020-03-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000005848 SCV002027640 pathogenic Charlevoix-Saguenay spastic ataxia 2021-09-05 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001847584 SCV002105082 pathogenic Hereditary spastic paraplegia 2016-12-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001851681 SCV002124857 pathogenic Spastic paraplegia 2023-11-06 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg2502*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2078 amino acid(s) of the SACS protein. This variant is present in population databases (rs281865118, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with autosomal recessive spastic ataxia of Charlevoix-Saguenay (PMID: 10655055, 30901567). This variant is also known as g.5254C>T. ClinVar contains an entry for this variant (Variation ID: 5513). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000005848 SCV004210031 pathogenic Charlevoix-Saguenay spastic ataxia 2023-02-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000005848 SCV004223820 pathogenic Charlevoix-Saguenay spastic ataxia 2023-11-14 criteria provided, single submitter clinical testing Variant summary: SACS c.7504C>T (p.Arg2502X) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. While this variant is not expected to result in nonsense mediated decay, it is predicted to disrupt the last 2,078 amino acids of the protein. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 251338 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7504C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (e.g., Engert_2000). These data indicate that the variant is very likely to be associated with disease. The following publication was ascertained in the context of this evaluation (PMID: 10655055). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research RCV000005848 SCV005044606 pathogenic Charlevoix-Saguenay spastic ataxia 2022-01-01 criteria provided, single submitter research
OMIM RCV000005848 SCV000026030 pathogenic Charlevoix-Saguenay spastic ataxia 2000-02-01 no assertion criteria provided literature only
GeneReviews RCV000005848 SCV000054638 not provided Charlevoix-Saguenay spastic ataxia no assertion provided literature only
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals RCV000005848 SCV000803693 pathogenic Charlevoix-Saguenay spastic ataxia 2017-10-25 no assertion criteria provided clinical testing

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