Submissions for variant NM_014363.6(SACS):c.12106A>T (p.Arg4036Ter)

dbSNP: rs2137561134

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382083	SCV001580713	pathogenic	Spastic paraplegia	2023-08-31	criteria provided, single submitter	clinical testing	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: 1070056). This variant has not been reported in the literature in individuals affected with SACS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg4036*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 544 amino acid(s) of the SACS protein.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003399200	SCV004121965	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-10-20	criteria provided, single submitter	clinical testing	Variant summary: SACS c.12106A>T (p.Arg4036X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. Although nonsense mediated decay is not predicted several variants downstream of this position have been classified as pathogenic by our laboratory and in ClinVar. The variant was absent in 250678 control chromosomes. To our knowledge, no occurrence of c.12106A>T in individuals affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.