ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1276C>T (p.Leu426Phe) (rs1060502227)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000516596 SCV000615385 uncertain significance not specified 2016-09-06 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000626922 SCV000747625 pathogenic Spasticity; Flexion contracture; Spastic diplegia; Tip-toe gait; Pes valgus 2017-01-01 criteria provided, single submitter clinical testing
Invitae RCV000644897 SCV000766615 likely pathogenic Spastic paraplegia 4, autosomal dominant 2017-11-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 426 of the SPAST protein (p.Leu426Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hereditary spastic paraplegia in a single family (PMID: 20214791). 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 C15"). A different missense substitution at this codon (p.Leu426Val) has been determined to be pathogenic (PMID: 10699187, 11843700, 15841487, 20718791, 22960362, 20932283, 11809724). This suggests that the leucine residue is critical for SPAST protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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