ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1164G>T (p.Lys388Asn) (rs1553316838)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000521931 SCV000618811 pathogenic not provided 2017-07-06 criteria provided, single submitter clinical testing The K388N variant in the SPAST gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The K388N variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The K388N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a conserved position within the ATPase domain. Missense variants in nearby residues (G385W, G385E, N386S, N386K, M390V, M390I, L391Q, L391P) have been reported in the Human Gene Mutation Database in association with spastic paraplegia (Stenson et al., 2014), supporting the functional importance of this region of the protein. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret K388N as a pathogenic variant.
Invitae RCV000528465 SCV000645340 pathogenic Spastic paraplegia 4, autosomal dominant 2017-10-07 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 388 of the SPAST protein (p.Lys388Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual with clinical features of hereditary spastic paraplegia (Invitae database). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Lys388Arg) has been determined to be pathogenic (PMID: 10699187, 20665701). This suggests that the lysine residue is critical for SPAST protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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