Submissions for variant NM_014363.6(SACS):c.10686_10689del (p.Phe3562fs)

dbSNP: rs779338945

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410430	SCV000486076	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2016-03-24	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000410430	SCV004209960	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-06-25	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000410430	SCV005044620	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
GeneDx	RCV004721347	SCV005328162	likely pathogenic	not provided	2023-12-28	criteria provided, single submitter	clinical testing	Reported previously with another SACS variant in an individual with cerebellar ataxia, impaired pursuit eye movement, and Babinski sign; parental testing to determine phase was not performed (PMID: 31429931); Frameshift variant predicted to result in abnormal protein length as the last 1018 amino acids are replaced with 7 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31429931)
Fulgent Genetics, Fulgent Genetics	RCV000410430	SCV005632162	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2024-06-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090648	SCV005829503	pathogenic	Spastic paraplegia	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe3562Leufs*8) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1018 amino acid(s) of the SACS protein. This variant is present in population databases (rs779338945, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with early onset cerebellar ataxia (PMID: 31429931). This variant is also known as c.10686_10689delAAAG (p.F3562Lfs*7). ClinVar contains an entry for this variant (Variation ID: 370696). 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. For these reasons, this variant has been classified as Pathogenic.