ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.1933T>A (p.Ser645Thr) (rs2099104)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000487696 SCV000252307 uncertain significance not provided 2018-12-07 criteria provided, single submitter clinical testing The S645T variant in the SPG7 gene has been reported previously in association with hereditary spastic paraplegia, however, the authors did not consider the variant disease causing as it was absent in at least one affected family member (Elleuch et al., 2006). The S645T variant is observed in 194/260002 (0.075%) alleles in large population cohorts (Lek et al., 2016). The S645T variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, we interpret S645T as a variant of uncertain significance,
Unit for Genetic & Epidemiological Research on Neurological Disorders,Instituto de Investigação e Inovação em Saúde RCV000515879 SCV000574483 uncertain significance Hereditary spastic paraplegia 2017-03-07 criteria provided, single submitter research
CeGaT Praxis fuer Humangenetik Tuebingen RCV000487696 SCV000575074 uncertain significance not provided 2016-12-01 criteria provided, single submitter clinical testing
Invitae RCV000640979 SCV000762588 uncertain significance Spastic paraplegia 7 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 645 of the SPG7 protein (p.Ser645Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs2099104, ExAC 0.2%). This variant has been reported in several individuals affected with hereditary spastic paraplegia (HSP) and in an unaffected control (PMID: 18200586, 28832565). This variant did not segregate with disease in at least one family affected with HSP (PMID: 16534102). ClinVar contains an entry for this variant (Variation ID: 215194). 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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