ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.814C>T (p.Arg272Cys) (rs374128662)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare 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.
Invitae RCV001380372 SCV001578405 pathogenic Spastic paraplegia 2020-07-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 272 of the SACS protein (p.Arg272Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with SACS-related conditions (PMID: 19892370, 30901567). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 504884). 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. For these reasons, this variant has been classified as Pathogenic.

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