Submissions for variant NM_025137.4(SPG11):c.6899T>C (p.Leu2300Pro) (rs371334506)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000224979	SCV000281762	pathogenic	Charcot-Marie-Tooth disease, axonal type 2X	2016-04-14	criteria provided, single submitter	research
GeneDx	RCV000498920	SCV000589883	likely pathogenic	not provided	2016-06-09	criteria provided, single submitter	clinical testing	The L2300P variant in the SPG11 gene has previously been reported in the compound heterozygous state in an individual with hereditary spastic paraplegia (Kara et al., 2016). The L2300P variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L2300P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, L2300P variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded
Invitae	RCV000706352	SCV000835396	likely pathogenic	Spastic paraplegia 11, autosomal recessive	2019-04-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with proline at codon 2300 of the SPG11 protein (p.Leu2300Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from pathogenic variants in individuals affected with hereditary spastic paraplegia (PMID: 27217339, 28554332). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 235890). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.