ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.623G>T (p.Ser208Ile) (rs911764681)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000522663 SCV000618957 likely pathogenic not provided 2017-07-14 criteria provided, single submitter clinical testing A variant that is likely pathogenic has been identified in the SACS gene. The S208I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The S208I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The S208I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret S208I as a likely pathogenic variant.
Counsyl RCV000674847 SCV000800248 uncertain significance Charlevoix-Saguenay spastic ataxia 2018-05-30 criteria provided, single submitter clinical testing
Invitae RCV001224412 SCV001396604 uncertain significance Spastic paraplegia 2019-06-20 criteria provided, single submitter clinical testing This sequence change replaces serine with isoleucine at codon 208 of the SACS protein (p.Ser208Ile). The serine residue is moderately conserved and there is a large physicochemical difference between serine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SACS-related conditions. ClinVar contains an entry for this variant (Variation ID: 450379). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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