Submissions for variant NM_014363.6(SACS):c.8716C>T (p.Arg2906Ter)

gnomAD frequency: 0.00002  dbSNP: rs750732115

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV001328754	SCV001519944	pathogenic	Charlevoix-Saguenay spastic ataxia	2024-03-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001386448	SCV001586676	pathogenic	Spastic paraplegia	2023-09-06	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. This sequence change creates a premature translational stop signal (p.Arg2906*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1674 amino acid(s) of the SACS protein. This variant is present in population databases (rs750732115, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with SACS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1027860).
Medical Genetics Laboratory, Tarbiat Modares University	RCV001328754	SCV001622770	pathogenic	Charlevoix-Saguenay spastic ataxia	2020-03-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001328754	SCV002027635	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001820019	SCV002064490	pathogenic	not provided	2019-08-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the SACS gene demonstrated the pathogenic sequence change, c.8716C>T, which results in the creation of a premature stop codon at amino acid position 2906, p.Arg2906*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated SACS protein with potentially abnormal function. This pathogenic sequence change has not been described in a patient with SACS-related ataxia. This sequence change has been described in the gnomAD database with a low population frequency of 0.0012% (rs750732115).
3billion, Medical Genetics	RCV001328754	SCV003841588	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). This variant was predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV001027860 / PMID: 34758253). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328754	SCV003844455	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-02-08	criteria provided, single submitter	clinical testing	Variant summary: SACS c.8716C>T (p.Arg2906X) 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 reported in association with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay in the HGMD database. The variant allele was found at a frequency of 1.2e-05 in 250936 control chromosomes. c.8716C>T has been reported in the literature as a homozygous genotype in at-least one individual affected with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (example, PMID: 35731353). Five 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. Based on the evidence outlined above, the variant was classified as pathogenic.
Genomics England Pilot Project, Genomics England	RCV001328754	SCV001760320	likely pathogenic	Charlevoix-Saguenay spastic ataxia		no assertion criteria provided	clinical testing