Submissions for variant NM_003119.4(SPG7):c.1198C>T (p.Arg400Trp)

gnomAD frequency: 0.00004  dbSNP: rs748024868

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494280	SCV000583107	uncertain significance	not provided	2017-05-25	criteria provided, single submitter	clinical testing	The R400W variant in the SPG7 gene has been reported previously in the heterozygous state in an individual with spastic paraplegia, however, it is unknown whether this individual was screened for variants in other genes associated with spastic paraplegia (Sanchez-Ferrero et al., 2013). The R400W variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R400W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R400W as a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323570	SCV004029486	uncertain significance	not specified	2023-07-19	criteria provided, single submitter	clinical testing	Variant summary: SPG7 c.1198C>T (p.Arg400Trp) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 248994 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1198C>T has been reported in the literature in individuals affected with sporadic spastic paraplegia and Amyotrophic lateral sclerosis (examples: Sanchez-Ferrero_2012 and Osmanovic_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32447552, 22571692). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV003507285	SCV004343529	uncertain significance	Hereditary spastic paraplegia 7	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 400 of the SPG7 protein (p.Arg400Trp). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis and/or hereditary spastic paraplegia (PMID: 22571692, 32447552). ClinVar contains an entry for this variant (Variation ID: 430325). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SPG7 protein function. 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.