Submissions for variant NM_025137.4(SPG11):c.6100C>T (p.Arg2034Ter)

gnomAD frequency: 0.00003  dbSNP: rs118203963

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000001168	SCV000253955	pathogenic	Hereditary spastic paraplegia 11	2023-12-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2034*) in the SPG11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SPG11 are known to be pathogenic (PMID: 19105190, 20110243, 22154821, 26556829). This variant is present in population databases (rs118203963, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 17322883, 18079167, 18332254, 18663179, 19438933). ClinVar contains an entry for this variant (Variation ID: 1109). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV000518418	SCV000615421	pathogenic	not provided	2017-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000518418	SCV000748243	pathogenic	not provided	2022-07-11	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27959697, 25525159, 17322883, 30510438, 18663179, 33059505)
Paris Brain Institute, Inserm - ICM	RCV000001168	SCV001451266	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000001168	SCV001523417	pathogenic	Hereditary spastic paraplegia 11	2020-06-17	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV002354145	SCV002659995	pathogenic	Inborn genetic diseases	2020-11-25	criteria provided, single submitter	clinical testing	The p.R2034* pathogenic mutation (also known as c.6100C>T), located in coding exon 32 of the SPG11 gene, results from a C to T substitution at nucleotide position 6100. This changes the amino acid from an arginine to a stop codon within coding exon 32. This alteration has been reported in the homozygous state in multiple patients with hereditary spastic paraplegia (Stromillo ML et al. J Neurol, 2011 Dec;258:2240-7; Stevanin G et al. Nat Genet, 2007 Mar;39:366-72; Stevanin G et al. Brain, 2008 Mar;131:772-84), and has also been confirmed in trans with a frameshift alteration in a family with autosomal recessive axonal Charcot-Marie-Tooth disease (Montecchiani C et al. Brain, 2016 Jan;139:73-85). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000001168	SCV002763749	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001168	SCV005398961	pathogenic	Hereditary spastic paraplegia 11	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with juvenile amyotrophic lateral sclerosis 5 (MIM#602099), Charcot-Marie-Tooth disease, axonal, type 2X (MIM#616668) and spastic paraplegia 11 (MIM#604360). The genotype-phenotype correlation is currently unestablished. (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variant comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. This variant has also been observed in multiple unrelated homozygous individuals with SPG11-related symptoms, as well as one individual with this variant and c.5866+1G>A (PMID: 18079167, VCGS internal database). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005007805	SCV005637868	pathogenic	Amyotrophic lateral sclerosis type 5; Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X	2024-04-14	criteria provided, single submitter	clinical testing
3billion	RCV000001168	SCV005903894	pathogenic	Hereditary spastic paraplegia 11	2023-12-15	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000001109 /PMID: 17322883). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000001168	SCV000021318	pathogenic	Hereditary spastic paraplegia 11	2015-11-10	no assertion criteria provided	literature only
GeneReviews	RCV000001168	SCV000058181	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only
OMIM	RCV000202373	SCV000257388	pathogenic	Charcot-Marie-Tooth disease axonal type 2X	2015-11-10	no assertion criteria provided	literature only
Baylor Genetics	RCV000414837	SCV000328861	pathogenic	Hereditary spastic paraplegia 11; Charcot-Marie-Tooth disease axonal type 2X	2015-05-27	no assertion criteria provided	clinical testing	Our laboratory reported three molecular diagnoses in CA2 (NM_000067.2, c.232+1G>A), MCCC2 (NM_022132.4, c.1015G>A), and SPG11 (NM_025137.3, c.6100C>T) in one individual with clinical features of global developmental delay, developmental regression, autistic features, intellectual disability, hypotonia, ataxia, dysmorphic features, short stature, microcephaly, hyperextensibility, failure to thrive, structural brain abnormalities, skeletal abnormalities, and limb malformation. The CA2 variant has been previously reported as disease-causing [PMID 1301935]. Heterozygotes would be expected to be asymptomatic carriers.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000518418	SCV001953931	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000518418	SCV001966328	pathogenic	not provided		no assertion criteria provided	clinical testing