Description
The c.1529C>T (p.A510V) alteration is located in coding exon 11 of the SPG7 gene. This alteration results from a C to T substitution at nucleotide position 1529, causing the alanine (A) at amino acid position 510 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD), the SPG7 c.1529C>T alteration was observed in 0.29% (820/282858) of total alleles studied, with two homozygotes observed, and a frequency of 0.48% (621/129168) in the European (non-Finnish) subpopulation. This mutation, which is the most frequently identified SPG7 mutation, has been detected in the homozygous and compound heterozygous states in multiple unrelated patients affected with SPG7-related spastic paraplegia and has been shown to segregate with disease in multiple families (Bonn, 2010; Roxburgh, 2013; Sánchez-Ferrero, 2013; Pfeffer, 2015; Choquet, 2016; Mancini, 2019). Variable expressivity has been reported, even among family members with the same genotype (Roxburgh, 2013). In addition, this variant is present at significantly higher rates in patients versus controls (Sanchez-Ferror, 2013; Mancini, 2019). This amino acid position is highly conserved in available vertebrate species. A yeast complementation assay demonstrated loss of of proteolytic activity of the A510V mutant protein under certain conditions (Bonn, 2010). The p.A510V alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
# | Sample | Method | Observation |
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Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
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1 | germline | unknown | 1 | not provided | not provided | | 1 | not provided | not provided | not provided |