Submissions for variant NM_014363.6(SACS):c.5719C>T (p.Arg1907Ter)

dbSNP: rs1485209013

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000672553	SCV000797666	pathogenic	Charlevoix-Saguenay spastic ataxia	2018-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000672553	SCV001983639	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-23	criteria provided, single submitter	clinical testing	Variant summary: SACS c.5719C>T (p.Arg1907X) 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 251294 control chromosomes. c.5719C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (example, Prodi_2013, Romano_2013, Criscuolo_2015, Pensabene_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genome-Nilou Lab	RCV000672553	SCV002027649	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002532128	SCV003442026	pathogenic	Spastic paraplegia	2023-07-07	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg1907*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2673 amino acid(s) of the SACS protein. This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 21410841, 22816526). ClinVar contains an entry for this variant (Variation ID: 556533). 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.
Baylor Genetics	RCV000672553	SCV004209890	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-03-12	criteria provided, single submitter	clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000672553	SCV005044642	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research