Submissions for variant NM_014363.6(SACS):c.12973C>T (p.Arg4325Ter)

gnomAD frequency: 0.00001  dbSNP: rs762947018

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Paris Brain Institute, Inserm - ICM	RCV000169272	SCV001451196	pathogenic	Charlevoix-Saguenay spastic ataxia		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000169272	SCV002027618	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000169272	SCV002060302	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-11-19	criteria provided, single submitter	clinical testing	NM_014363.4(SACS):c.12973C>T(R4325*) is a nonsense variant classified as pathogenic in the context of autosomal recessive spastic ataxia of Charlevoix-Saguenay. R4325* has been observed in cases with relevant disease (PMID: 16944349, 27142713, 21665375, 31475473). Functional assessments of this variant are not available in the literature. R4325* has been observed in population frequency databases (gnomAD: SAS 0.003%). In summary, NM_014363.4(SACS):c.12973C>T(R4325*) is a nonsense variant variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850396	SCV002243345	pathogenic	Spastic paraplegia	2023-10-14	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg4325*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 255 amino acid(s) of the SACS protein. This variant is present in population databases (rs762947018, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 16944349, 21993619, 23280630). ClinVar contains an entry for this variant (Variation ID: 188912). This variant disrupts a region of the SACS protein in which other variant(s) (p.Tyr4538*) have been determined to be pathogenic (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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000169272	SCV004209906	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-09-26	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000169272	SCV004698113	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-02-28	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_STR,PM2_SUP
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000169272	SCV005061907	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Department of Rehabilitation Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea	RCV000169272	SCV000882755	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2019-02-11	no assertion criteria provided	research	The proband has another variant, NM_014363.5: c.11101T>C (p.Trp3701Arg).