Submissions for variant NM_025137.4(SPG11):c.4790G>A (p.Trp1597Ter)

gnomAD frequency: 0.00001  dbSNP: rs753920931

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550739	SCV000642244	pathogenic	Hereditary spastic paraplegia 11	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp1597*) 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 (rs753920931, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal recessive hereditary spastic paraplegia (PMID: 19917823). ClinVar contains an entry for this variant (Variation ID: 466534). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000550739	SCV002026388	pathogenic	Hereditary spastic paraplegia 11	2021-11-16	criteria provided, single submitter	clinical testing	Criteria applied: PVS1, PM3, PM2_SUP
Ambry Genetics	RCV002341340	SCV002639525	pathogenic	Inborn genetic diseases	2021-08-19	criteria provided, single submitter	clinical testing	The p.W1597* variant (also known as c.4790G>A), located in coding exon 28 of the SPG11 gene, results from a G to A substitution at nucleotide position 4790. This changes the amino acid from a tryptophan to a stop codon within coding exon 28. This variant was detected in a cohort of early onset complicated hereditary spastic paraplegia (HSP) patients; however, clinical details were limited (Schüle R et al. J Neurol Neurosurg Psychiatry, 2009 Dec;80:1402-4). This alteration has also been reported in the compound heterozygous state in a patient with spastic paraparesis, learning difficulties and a thin corpus callosum (Murugan A et al. Eur J Med.Case Rep, 2017; 1(3):122-125). 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	RCV000550739	SCV002763896	pathogenic	Hereditary spastic paraplegia 11		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004689788	SCV005184606	pathogenic	Hereditary spastic paraplegia	2024-05-24	criteria provided, single submitter	clinical testing	Variant summary: SPG11 c.4790G>A (p.Trp1597X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 8e-06 in 251332 control chromosomes. c.4790G>A has been reported in the literature in at-least one individual affected with Hereditary Spastic Paraplegia (Murugan et al). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (Murugan et al). ClinVar contains an entry for this variant (Variation ID: 466534). Based on the evidence outlined above, the variant was classified as pathogenic.