Submissions for variant NM_025137.4(SPG11):c.5599G>A (p.Glu1867Lys)

gnomAD frequency: 0.00008  dbSNP: rs372419484

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642554	SCV000764240	uncertain significance	Hereditary spastic paraplegia 11	2022-03-17	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1867 of the SPG11 protein (p.Glu1867Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 534857). 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 tolerated. 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 Diagnostics Laboratory, The Hospital for Sick Children	RCV001849018	SCV002105735	uncertain significance	Hereditary spastic paraplegia	2019-01-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467958	SCV002763813	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467959	SCV002763814	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000642554	SCV002763815	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003258903	SCV003979960	uncertain significance	Inborn genetic diseases	2023-06-14	criteria provided, single submitter	clinical testing	The c.5599G>A (p.E1867K) alteration is located in exon 30 (coding exon 30) of the SPG11 gene. This alteration results from a G to A substitution at nucleotide position 5599, causing the glutamic acid (E) at amino acid position 1867 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GenomeConnect - Invitae Patient Insights Network	RCV001535674	SCV001749737	not provided	Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-12-2019 by 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.