Submissions for variant NM_025137.4(SPG11):c.2716del (p.Gln906fs)

dbSNP: rs312262747

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV001659927	SCV001880685	pathogenic	not provided	2020-11-24	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000034198	SCV002188001	pathogenic	Hereditary spastic paraplegia 11	2023-12-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln906Serfs*15) 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 (rs312262747, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of hereditary spastic paraplegia (PMID: 19105190, 26755014). ClinVar contains an entry for this variant (Variation ID: 41297). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000034198	SCV002764031	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114210	SCV003801202	pathogenic	Hereditary spastic paraplegia	2023-01-17	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.2716delC (p.Gln906SerfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar. The variant allele was found at a frequency of 4e-06 in 251404 control chromosomes (gnomAD). c.2716delC has been reported in the literature in individuals affected with Hereditary Spastic Paraplegia (example: Denora_2009). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001659927	SCV003821718	pathogenic	not provided	2022-11-11	criteria provided, single submitter	clinical testing
Lifecell International Pvt. Ltd	RCV000034198	SCV003925692	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing	A Homozygote Frameshift variant c.2716delC in Exon 15 of the SPG11 gene that results in the amino acid substitution p.Gln906fs*15 was identified. The observed variant is novel in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID: 41297]. This variant is reported by Patel et al., 2016 for heredity Spastic Paraplegia. For these reasons, this variant has been classified as Pathogenic.
GeneReviews	RCV000034198	SCV000058136	not provided	Hereditary spastic paraplegia 11		no assertion provided	literature only