ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1637G>A (p.Gly546Glu) (rs786204057)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000167918 SCV000218566 pathogenic Spastic paraplegia 4, autosomal dominant 2018-10-17 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 546 of the SPAST protein (p.Gly546Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with hereditary spastic paraplegia (PMID: Invitae). The observation of one or more missense substitutions at this codon (p.Gly546Glu and p.Gly546Arg) in affected individuals suggests that this may be a clinically significant residue (PMID: 27260292, Invitae). This missense change is located within a functionally conserved AAA domain of the SPAST protein (PMID: 9695811, 18410514) and a high percentage (~85%) of previously reported SPAST missense mutations have been found within this domain (PMID: 18701882). These observations suggest that a novel missense substitution within this domain may affect protein function, but experiments have not been done to test this possibility. For these reasons, this variant has been classified as Pathogenic.

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