ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.7528G>A (p.Ala2510Thr) (rs111920492)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics RCV000243536 SCV000312160 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000710207 SCV000576775 uncertain significance not provided 2017-04-19 criteria provided, single submitter clinical testing The A2510T variant in the SACS gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A2510T variant is observed in 127/66710 (0.19%) alleles from individuals of European background, in the ExAC dataset (Lek et al., 2016). The A2510T 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 A2510T as a variant of uncertain significance.
Athena Diagnostics Inc RCV000710207 SCV000614977 uncertain significance not provided 2018-05-11 criteria provided, single submitter clinical testing
Invitae RCV000546423 SCV000629481 uncertain significance Spastic paraplegia 2017-10-17 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2510 of the SACS protein (p.Ala2510Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs111920492, ExAC 0.2%). This variant has not been reported in the literature in individuals with SACS-related disease. ClinVar contains an entry for this variant (Variation ID: 260399). 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, 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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