Submissions for variant NM_014363.6(SACS):c.6355C>T (p.Arg2119Ter)

dbSNP: rs766711286

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672257	SCV000797348	pathogenic	Charlevoix-Saguenay spastic ataxia	2018-01-23	criteria provided, single submitter	clinical testing
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000672257	SCV000891693	pathogenic	Charlevoix-Saguenay spastic ataxia	2017-12-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672257	SCV001519398	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-03-05	criteria provided, single submitter	clinical testing	Variant summary: SACS c.6355C>T (p.Arg2119X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250894 control chromosomes. c.6355C>T has been reported in the literature in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (example, Hara_2007, Hamza_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. One submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV001387162	SCV001587721	pathogenic	Spastic paraplegia	2022-12-16	criteria provided, single submitter	clinical testing	This premature translational stop signal has been observed in individual(s) with clinical features of hereditary spastic paraplegia (PMID: 17516465, 26068213, 26288984). 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.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. ClinVar contains an entry for this variant (Variation ID: 556270). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2119*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2461 amino acid(s) of the SACS protein.
Genome-Nilou Lab	RCV000672257	SCV002027646	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000672257	SCV004209929	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-08-20	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000672257	SCV002086242	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-02-18	no assertion criteria provided	clinical testing