ClinVar Genomic variation as it relates to human health

This variant was classified as: Uncertain significance. The available evidence favors the pathogenic nature of this variant, however the currently available data is insufficient to conclusively support its pathogenic nature. Thus this variant is classified as Uncertain significance - favor pathogenic. The following ACMG criteria were applied in classifying this variant: PP3,PP5.

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.

DNA sequence analysis of the SPG11 gene demonstrated a c.5381T>C in exon 30, results in an amino acid change, p.Leu1794Pro. The p.Leu1794Pro change affects a highly conserved amino acid residue located in a domain of the SPG11 protein that is not known to be functional. The p.Leu1794Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been reported in the compound heterozygous state with a truncating variant in three unrelated families with spastic paraplegia (Lynch et al., 2016). This sequence change has been described in the gnomAD database with a global population frequency of 0.0057% (dbSNP rs201689565).

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.63). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000374112). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

PM3, PP4, PP3, PM2_SUP, PP1

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1794 of the SPG11 protein (p.Leu1794Pro). This variant is present in population databases (rs201689565, gnomAD 0.01%). This missense change has been observed in individuals with hereditary spastic paraplegia (PMID: 26374131, 31407473; Invitae). ClinVar contains an entry for this variant (Variation ID: 374112). 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) performed at Invitae indicates that this missense variant is expected to disrupt SPG11 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.

This sequence change in SPG11 is predicted to replace leucine with proline at codon 1794, p.(Leu1794Pro). The leucine residue is highly conserved (100 vertebrates, UCSC), and is not located in an annotated functional domain. There is a moderate physicochemical difference between leucine and proline. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.01% (15/128,650 alleles) in the European (non-Finnish) population, which is consistent with a recessive disease. The variant has been identified in a homozygous state and compound heterozygous with a second pathogenic allele in multiple cases diagnosed with complicated/pure hereditary spastic paraplegia (HSP) and segregates with the condition in at least one family (PMID: 26374131, 31407473, 35254204, 36139378). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.897). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2_Supporting, PP1, PP3.

The c.5381T>C (p.L1794P) alteration is located in exon 30 (coding exon 30) of the SPG11 gene. This alteration results from a T to C substitution at nucleotide position 5381, causing the leucine (L) at amino acid position 1794 to be replaced by a proline (P). Based on data from gnomAD, the C allele has an overall frequency of 0.006% (16/281906) total alleles studied. The highest observed frequency was 0.012% (15/128650) of European (non-Finnish) alleles. This mutation has been reported in the homozygous and compound heterozygous state in individuals with spastic paraplegia (Lynch, 2015; Krenn, 2020; Doleckova, 2022; Peri, 2022). It was also identified in the homozygous state in an individual with childhood-onset dystonia (Zech, 2020) and in the heterozygous state in an individual with amyotrophic lateral sclerosis with no second SPG11 variant (Krüger, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27790088, 26374131, 31407473, 34426522, 31589614, 33098801, 35254204, 35872528, 36549973, 36139378, 35906604, 34983064)

Variant summary: SPG11 c.5381T>C (p.Leu1794Pro) results in a non-conservative amino acid change in 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 4.8e-05 in 250508 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SPG11 causing Hereditary Spastic Paraplegia, Type 11 (4.8e-05 vs 0.0011), allowing no conclusion about variant significance. c.5381T>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Hereditary Spastic Paraplegia, Type 11 (e.g. Lynch_2016, Zech_2020, Krenn_2020, Peric_2022). These data indicate that the variant is very likely to be associated with disease. 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: 31407473, 26374131, 36139378, 33098801). ClinVar contains an entry for this variant (Variation ID: 374112). Based on the evidence outlined above, the variant was classified as pathogenic.

Variant confirmed as disease-causing by referring clinical team

Variant interpreted as Pathogenic and reported on 12-19-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.