ClinVar Miner

Submissions for variant NM_014363.6(SACS):c.10954C>A (p.Pro3652Thr) (rs201505036)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000466695 SCV000552974 uncertain significance Spastic paraplegia 2017-08-10 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 3652 of the SACS protein (p.Pro3652Thr). The proline residue is moderately conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs201505036, ExAC 0.02%). This variant has been reported on an allele carrying a second missense mutation (c.10907G>A, p.Arg3636Gln) in 4 Belgian families affected with autosomal recessive spastic ataxia of Charlevoix-Saguenay. In 3 of these families, this double mutant allele occurred in the compound heterozygous state with an additional missense or frameshift mutation on the opposite allele, and in 1 individual it occurred in the homozygous state. Haplotype analysis revealed that these families were distantly related and carried the same founder mutation (PMID: 20876471). ClinVar contains an entry for this variant (Variation ID: 411693. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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