Submissions for variant NM_014363.6(SACS):c.814C>T (p.Arg272Cys)

gnomAD frequency: 0.00001  dbSNP: rs374128662

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824757	SCV000711751	likely pathogenic	Hereditary ataxia	2016-10-28	criteria provided, single submitter	clinical testing	The p.Arg272Cys variant in SACS has been reported in 2 individuals with ataxia a nd segregated with the disease in 3 affected individuals from each family. Affec ted members from one of the families were homozygous whereas affected individual s from the other family were compound heterozygous (Guernsey 2010), while unaffe cted individuals were all heterozygous or did not have the p.Arg272Cys variant. The variant has been identified in 1/8600 European American chromosomes by the N HLBI Exome Sequencing Project and was absent from >60,000 individuals in the ExA C database (http://evs.gs.washington.edu/EVS/; http://exac.broadinstitute.org/; dbSNP rs374128662). Although this variant has been seen in the general populatio n, its frequency is low enough to be consistent with a recessive carrier frequen cy. Computational prediction tools and conservation analysis suggest that the p. Arg272Cys variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, although additional studies a re required to fully establish its clinical significance, the p.Arg272Cys varian t is likely pathogenic.
Counsyl	RCV000612398	SCV000792231	likely pathogenic	Charlevoix-Saguenay spastic ataxia	2017-06-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000612398	SCV001360827	pathogenic	Charlevoix-Saguenay spastic ataxia	2019-01-24	criteria provided, single submitter	clinical testing	Variant summary: SACS c.814C>T (p.Arg272Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 246202 control chromosomes. c.814C>T has been reported in the literature in multiple individuals affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay and in families with segregation data (Guernsey_2010, Thiffaul_2013). 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. 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380372	SCV001578405	pathogenic	Spastic paraplegia	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the SACS protein (p.Arg272Cys). This variant is present in population databases (rs374128662, gnomAD 0.003%). This missense change has been observed in individual(s) with SACS-related conditions (PMID: 19892370, 30901567). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SACS protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001591363	SCV001814935	pathogenic	not provided	2020-08-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Lariviere et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30866998, 23250129, 30901567, 29945973, 31493945, 19892370, 23280630)
Genome-Nilou Lab	RCV000612398	SCV002027674	pathogenic	Charlevoix-Saguenay spastic ataxia	2021-09-05	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001591363	SCV004229958	pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 30866998, 29945973). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	RCV000612398	SCV005044553	pathogenic	Charlevoix-Saguenay spastic ataxia	2022-01-01	criteria provided, single submitter	research
Baylor Genetics	RCV000612398	SCV005055564	pathogenic	Charlevoix-Saguenay spastic ataxia	2023-11-09	criteria provided, single submitter	clinical testing