Submissions for variant NM_025137.4(SPG11):c.6952C>T (p.Arg2318Cys)

gnomAD frequency: 0.00004  dbSNP: rs377341108

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642562	SCV000764249	uncertain significance	Hereditary spastic paraplegia 11	2022-05-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2318 of the SPG11 protein (p.Arg2318Cys). This variant is present in population databases (rs377341108, gnomAD 0.006%). This missense change has been observed in individual(s) with SPG11-related conditions (PMID: 33589474). ClinVar contains an entry for this variant (Variation ID: 534865). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000642562	SCV001367664	uncertain significance	Hereditary spastic paraplegia 11	2018-11-28	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
Baylor Genetics	RCV001331386	SCV001523419	uncertain significance	Amyotrophic lateral sclerosis type 5	2020-09-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001849020	SCV002105773	uncertain significance	Hereditary spastic paraplegia	2021-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002360576	SCV002663807	uncertain significance	Inborn genetic diseases	2022-04-15	criteria provided, single submitter	clinical testing	The p.R2318C variant (also known as c.6952C>T), located in coding exon 38 of the SPG11 gene, results from a C to T substitution at nucleotide position 6952. The arginine at codon 2318 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been detected in an individual with amyotrophic lateral sclerosis (ALS); however, clinical details were limited (Shepheard SR et al. J Neurol Neurosurg Psychiatry, 2021 05;92:510-518). This amino acid position is not well conserved in available vertebrate species, and cysteine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV001331386	SCV002763463	uncertain significance	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467963	SCV002763474	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000642562	SCV002763485	uncertain significance	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing