Submissions for variant NM_025137.4(SPG11):c.6899T>G (p.Leu2300Arg)

dbSNP: rs371334506

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000679859	SCV000807219	uncertain significance	Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11	2017-09-01	criteria provided, single submitter	clinical testing	Likely pathogenicity based on finding it once in our laboratory in trans with a nonsense variant [E1630X] in a 10-year-old male with convulsions, increased muscle tone and awkward gait
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806086	SCV000946067	likely pathogenic	Hereditary spastic paraplegia 11	2024-02-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2300 of the SPG11 protein (p.Leu2300Arg). This variant is present in population databases (rs371334506, gnomAD 0.002%). This missense change has been observed in individual(s) with dopa responsive dystonia (PMID: 30363882). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 560924). 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%. This variant disrupts the p.Leu2300 amino acid residue in SPG11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27217339, 28554332). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV002467984	SCV002763639	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467985	SCV002763641	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000806086	SCV002763642	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing