ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1496G>A (p.Arg499His) (rs878854991)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000230990 SCV000290034 pathogenic Spastic paraplegia 4, autosomal dominant 2019-01-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 499 of the SPAST protein (p.Arg499His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This sequence change has been reported in multiple individuals and families affected with spastic paraplegia (PMID: 16009769, 18701882, 20562464, 16682546, 16055926, 25045380, 10610178). ClinVar contains an entry for this variant (Variation ID: 240950). This amino acid substitution falls in the central ATPase domain of spastin (AAA domain) involved in ATP hydrolysis, where most sequence changes reported to cause spastic paraplegia cluster (PMID: 18701882). A different amino acid substitution at this position (Arg499Cys), also reported in spastic paraplegia patients (PMID: 11309678, 11809724, 10699187, 12161613, 16055926), has been shown to abolish spastin ATPase activity (PMID: 15716377). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000713467 SCV000339060 uncertain significance not provided 2016-01-29 criteria provided, single submitter clinical testing
Institute of Human Genetics,Klinikum rechts der Isar RCV000230990 SCV000680389 pathogenic Spastic paraplegia 4, autosomal dominant 2017-11-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000623007 SCV000741401 likely pathogenic Inborn genetic diseases 2016-03-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000230990 SCV000743204 pathogenic Spastic paraplegia 4, autosomal dominant 2017-07-28 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000713467 SCV000844078 pathogenic not provided 2017-02-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV000230990 SCV000992839 pathogenic Spastic paraplegia 4, autosomal dominant 2017-12-31 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000230990 SCV000745629 pathogenic Spastic paraplegia 4, autosomal dominant 2016-10-14 no assertion criteria provided clinical testing
Molecular Genetics Laboratory,BC Children's and BC Women's Hospitals RCV000230990 SCV000898159 pathogenic Spastic paraplegia 4, autosomal dominant 2018-08-21 no assertion criteria provided clinical testing

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