Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000798580 | SCV000938203 | uncertain significance | Hereditary spastic paraplegia 7 | 2018-07-07 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has been observed in individuals affected with spastic paraplegia (PMID: 22964162, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glutamine at codon 470 of the SPG7 protein (p.Arg470Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. |
| Paris Brain Institute, |
RCV000798580 | SCV001451046 | pathogenic | Hereditary spastic paraplegia 7 | criteria provided, single submitter | clinical testing | ||
| Ambry Genetics | RCV002537998 | SCV003748297 | uncertain significance | Inborn genetic diseases | 2022-09-08 | criteria provided, single submitter | clinical testing | The c.1409G>A (p.R470Q) alteration is located in exon 10 (coding exon 10) of the SPG7 gene. This alteration results from a G to A substitution at nucleotide position 1409, causing the arginine (R) at amino acid position 470 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003323725 | SCV004029485 | uncertain significance | not specified | 2023-07-27 | criteria provided, single submitter | clinical testing | Variant summary: SPG7 c.1409G>A (p.Arg470Gln) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1409G>A has been reported in the literature in two homozygous siblings affected with Hereditary Spastic Paraplegia 7 and optical nerve atrophy (example, van Gassen_2012). However, the authors state that the influence of other variants cannot be ruled out given the predominant visual phenotype of the siblings, so this report does not provide unequivocal conclusions about association of the variant with Hereditary Spastic Paraplegia 7. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 22964162). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |