Submissions for variant NM_025137.4(SPG11):c.2146C>T (p.Gln716Ter)

dbSNP: rs312262737

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000034186	SCV000260934	pathogenic	Hereditary spastic paraplegia 11	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln716*) 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 (rs312262737, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hereditary spastic paraplegia (PMID: 20390432, 27217339, 27544499). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 41285). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000034186	SCV000391298	likely pathogenic	Hereditary spastic paraplegia 11	2017-04-27	criteria provided, single submitter	clinical testing	The SPG11 c.2146C>T (p.Gln716Ter) variant is a stop gained variant that is predicted to result in prematire termination of the protein. The p.Gln716Ter variant has been reported in two studies in which it is found in a total of four patients with spastic paraplegia including in three in a homozygous state (including two siblings) and in one in a compound heterozygous state (Southgate et al. 2010; Kara et al. 2016). The p.Gln716Ter variant was also detected in a heterozygous state in the unaffected parents of the homozygous siblings (Southgate et al. 2010). The p.Gln716Ter variant was absent from 180 controls and is reported at a frequency of 0.00012 in the European American population of the Exome Sequencing Project. This frequency is based on one allele only but in an area of good sequence coverage so the variant is presumed to be rare. Due to the potential impact of stop-gained variants and evidence from the literature, the p. Gln716Ter variant is classified as likely pathogenic for the autosomal recessive form of spastic paraplegia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000414282	SCV000491253	pathogenic	not provided	2023-03-20	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: 25525159, 27544499, 20390432, 30212743, 31069529, 27217339)
3billion	RCV001807747	SCV002058619	pathogenic	Charcot-Marie-Tooth disease axonal type 2X	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 observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000041285, PMID:20390432). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000034186	SCV004047598	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing	The stop gained variant c.2146C>T (p.Gln716Ter) in SPG11 gene has been reported previously in homozygous state in individuals affected with hereditary spastic paraplegia (Kara, Eleanna et al., 2016) and segregated with disease in an affected family (Southgate L et al., 2010). The p.Gln716Ter variant has allele frequency 0.0003% in gnomAD exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely_pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000034186	SCV000058124	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000034186	SCV000747827	uncertain significance	Hereditary spastic paraplegia 11	2015-11-03	flagged submission	clinical testing	The observed variant c.2146C>T (p.Gln716Ter) is not reported in 1000 Genomes and its minor allele frequency ExAC databases is 0.000008252. The in silico prediction of the variant is disease causing by MutationTaster2.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV001807747	SCV002569374	uncertain significance	Charcot-Marie-Tooth disease axonal type 2X	2022-02-01	flagged submission	clinical testing	A heterozygous nonsense variation in exon 11 of the SPG11 gene that results in a stop codon and premature truncation of the protein at codon 716 (p.Gln716Ter) was detected. The observed variation has previously been reported in patients affected with hereditary spastic paraplegia . The p.Gln716Ter variant has not been reported in the 1000 genomes and gnomAD database. The reference codon is conserved across species. In summary, the varint meets the criteria to be classified as variant of uncertain significance.