Submissions for variant NM_025137.4(SPG11):c.6305A>G (p.Asp2102Gly)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003329991	SCV004036920	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; In addition, in silico predictors suggest the missense change may have a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV005103923	SCV005819593	uncertain significance	Hereditary spastic paraplegia 11	2024-08-14	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 2102 of the SPG11 protein (p.Asp2102Gly). This variant is present in population databases (rs531345715, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 2580796). Invitae Evidence 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 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 SPG11 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.