ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1168A>G (p.Met390Val) (rs797044850)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000190649 SCV000244089 pathogenic Inborn genetic diseases 2014-10-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: POSITIVE: Relevant Alteration(s) Detected
Athena Diagnostics Inc RCV000478313 SCV000615380 pathogenic not provided 2017-04-28 criteria provided, single submitter clinical testing
GeneDx RCV000478313 SCV000568707 pathogenic not provided 2017-01-20 criteria provided, single submitter clinical testing The M390V variant in the SPAST gene has been reported previously in association with childhood onset hereditary spastic paraplegia, including in a family where the variant segregated with disease in four affected family members across two generations (Tang et al., 2004; Alvarez et al., 2010; Park et al., 2015). The M390V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The M390V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position, within the ATPase domain, 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 M390V as a pathogenic variant.
Invitae RCV000206286 SCV000260546 pathogenic Spastic paraplegia 4, autosomal dominant 2015-09-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 390 of the SPAST protein (p.Met390Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases and has been reported in patients with hereditary spastic paraplegia (HSP). In one family, this variant co-segregated with HSP in 4 individuals and was absent from 1 tested individual without disease (PMID: 14732620). In a second family, this variant was confirmed to be de novo in a young child with apparently sporadic HSP (PMID: 20932283). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this is a rare missense variant that is absent from the general population and reported to co-segregate with disease in two independent families. For these reasons, this variant has been classified as Pathogenic.

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