Table 1.
Rare heterozygous non-silent variants in the SPG7 gene predicted to be deleterious identified in 214 European ALS patients
| Sample | Chromosomal position GRCh37/hg19 | Exon | Nucleotide change | Amino acid change | dbSNP | MAF | Prediction tools | ACMG guidelines | Predicted consequence on protein level | Previously described in | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| SIFT | PolyPhen-2 | ||||||||||
| MD087 | 16:89598369 | 8 | c.1045G > A | p.(G349S) | rs141659620 | 0.001437 | Deleterious | Probably damaging | Pathogenic | Effect on P-loop (Walker A motif), hence on nucleotide binding and potentially on hydrolysis (coupling of the hydrolysis state) | ALS [26], CA [37], HSP [28], UMN [24] |
| VALS008 | 16:89598918 | 9 | c.1198C > T | p.(R400W) | rs748024868 | – | Deleterious | Probably damaging | Likely pathogenic | Destabilization of N-terminal domain and supracomplex formation (mutation is part of the hexamer interface) | HSP [12] |
|
TALS012-01 VALS020 VALS125 |
16:89613073 | 11 | c.1457G > A | p.(R486Q) | rs111475461 | 0.007232 | Deleterious | Benign | Uncertain significance | Similar effect as p.(A510V) possible. Destabilization of α-helical bundle and sensor 2 | HSP [19] |
|
TALS002-01 VALS093 MD075 |
16:89613145 | 11 | c.1529C > T | p.(A510V) | rs61755320 | 0.004004 | Deleterious | Probably damaging | Pathogenic | May sterically disturb interactions between helices 5 and 6, and destabilize the α-helical bundle, hence have an effect on opening/closing and complex formation, may also affect sensor 2 (aa518-520, GAP motif) that couples hydrolysis state to oligomerization state | ALS [27], CA [37], HSP [12, 19, 28], UMN [24] |
| MD018 | 16:89613169 | 11a | c.1552 + 1G > T | – | rs141644720 | 0.00006002 | – | – | Pathogenic | Altered α-helical bundle (aa483-556[stop]), hence effect on opening/closing and supracomplex formation, peptidase domain is missing | HSP [18] |
Reference sequence used: NM_003119.2. Only variants in the coding region of SPG7 and canonical ± 1 or 2 splice site variants are given
All variants are located in the AAA+ domain (amino acid residues 305–565) [14] of paraplegin
aa amino acids, ACMG guidelines interpretation of sequence variants according to the American College of Medical Genetics and Genomics guidelines [13], ALS amyotrophic lateral sclerosis, CA cerebellar ataxia, HSP hereditary spastic paraplegia, MAF minor allele frequency in European (non-Finnish) population according to Exome Aggregation Consortium Browser (Beta), SIFT according to Alamut Visual version 2.11, UMN upper motor neuron syndrome
aIntron 11