Submissions for variant NM_025137.4(SPG11):c.935G>A (p.Gly312Asp)

gnomAD frequency: 0.00005  dbSNP: rs774273136

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481547	SCV000572707	uncertain significance	not provided	2017-02-03	criteria provided, single submitter	clinical testing	The G312D variant in the SPG11 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G312D variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G312D 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 in mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G312D as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000686983	SCV000814529	uncertain significance	Hereditary spastic paraplegia 11	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 312 of the SPG11 protein (p.Gly312Asp). This variant is present in population databases (rs774273136, gnomAD 0.03%). 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: 423068). 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) indicates that this missense variant is expected to disrupt SPG11 protein function with a positive predictive value of 80%. 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.
Genome-Nilou Lab	RCV002467834	SCV002764194	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467835	SCV002764196	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000686983	SCV002764197	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002526648	SCV003754675	uncertain significance	Inborn genetic diseases	2021-06-18	criteria provided, single submitter	clinical testing	The c.935G>A (p.G312D) alteration is located in exon 5 (coding exon 5) of the SPG11 gene. This alteration results from a G to A substitution at nucleotide position 935, causing the glycine (G) at amino acid position 312 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.