Submissions for variant NM_025137.4(SPG11):c.6091C>T (p.Arg2031Ter)

dbSNP: rs147713329

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001092496	SCV001249034	pathogenic	not provided	2017-09-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001331384	SCV001523416	pathogenic	Amyotrophic lateral sclerosis type 5	2019-03-26	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease causing [PMID 18408091, 29691679, 25525159]
3billion	RCV000034241	SCV002058905	pathogenic	Hereditary spastic paraplegia 11	2022-01-03	criteria provided, single submitter	clinical testing	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 (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000041340, PMID:18408091). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001847636	SCV002105746	pathogenic	Hereditary spastic paraplegia	2016-12-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034241	SCV002158212	pathogenic	Hereditary spastic paraplegia 11	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg2031*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 18408091, 29691679). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41340). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001092496	SCV002588297	pathogenic	not provided	2022-04-27	criteria provided, single submitter	clinical testing	Reported in several members of one family with hereditary spastic paraplegia who also harbor a frameshift variant on the opposite allele (in trans) (Lee et al., 2008); 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: 25525159, 31227335, 31692161, 29691679, 18408091)
Genome-Nilou Lab	RCV001331384	SCV002763757	pathogenic	Amyotrophic lateral sclerosis type 5		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000034241	SCV002763758	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001092496	SCV002771252	pathogenic	not provided	2022-10-13	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. This variant segregates with disease in multiple families. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001847636	SCV004122485	pathogenic	Hereditary spastic paraplegia	2023-10-31	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.6091C>T (p.Arg2031X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, a commonly known mechanism for disease. The variant was absent in 251360 control chromosomes (gnomAD). c.6091C>T has been reported in the literature in multiple individuals affected with Hereditary Spastic Paraplegia, Type 11 (e.g. Denora_2009). These data indicate that the variant is very likely to be associated with disease. The following publication have been ascertained in the context of this evaluation (PMID: 19105190). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000034241	SCV005073842	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing	The stop gained variant c.6091C>T (p.Arg2031Ter) in the SPG11 gene has been reported in the compound heterozygous and homozygous state in individuals affected with hereditary spastic paraplegia (Travaglini et al., 2018; Kara et al., 2016). The variant is absent in gnomAD Exomes. It has been submitted to ClinVar as Pathogenic (Multiple submitters). This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed.
GeneReviews	RCV000034241	SCV000058180	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only