Submissions for variant NM_014363.6(SACS):c.13132C>T (p.Arg4378Ter)

dbSNP: rs747868017

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001865265	SCV002243937	pathogenic	Spastic paraplegia	2024-10-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg4378*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 202 amino acid(s) of the SACS protein. This variant is present in population databases (rs747868017, gnomAD 0.0009%). This premature translational stop signal has been observed in individuals with spastic ataxia of Charlevoix-Saguenay (PMID: 20852969, 30638817). ClinVar contains an entry for this variant (Variation ID: 370756). This variant disrupts a region of the SACS protein in which other variant(s) (p.Tyr4538*) have been determined to be pathogenic (internal data). 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.
3billion	RCV000410263	SCV002521153	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by less than 10%. The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 30638817). The variant has been reported to be associated with SACS related disorder (ClinVar ID: VCV000370756 / PMID: 20852969). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000410263	SCV005061928	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Fulgent Genetics, Fulgent Genetics	RCV000410263	SCV005632149	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000410263	SCV000486150	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2016-04-12	no assertion criteria provided	clinical testing	This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact [e-mail].