Submissions for variant NM_014363.6(SACS):c.12603C>A (p.Tyr4201Ter)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003062567	SCV003442024	pathogenic	Spastic paraplegia	2022-09-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr4201*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 379 amino acid(s) of the SACS protein. This variant is not present in population databases (gnomAD no frequency). 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.Leu4303*) have been determined to be pathogenic (PMID: 16944349, 23497566, 26288984; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23497566).
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV004817193	SCV005061916	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research