ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.1033C>T (p.Arg345Trp) (rs776156836)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466492 SCV000552968 uncertain significance Spastic paraplegia 2016-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 345 of the SACS protein (p.Arg345Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs776156836, ExAC 0.02%) but has not been reported in the literature in individuals with a SACS-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000519338 SCV000619216 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing The R345W variant in the SACS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, this variant is observed in 4/16510 (0.02%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). [The R345W 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. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret R345W as a variant of uncertain significance.

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