ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.1478_1482del (p.Leu493fs)

dbSNP: rs758015273
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000814482 SCV000954895 pathogenic Hereditary spastic paraplegia 11 2024-01-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu493Trpfs*63) 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 (rs758015273, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with SPG11-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 657795). For these reasons, this variant has been classified as Pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV001849115 SCV002105665 likely pathogenic Hereditary spastic paraplegia 2017-12-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000814482 SCV002764131 likely pathogenic Hereditary spastic paraplegia 11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001849115 SCV004100182 pathogenic Hereditary spastic paraplegia 2023-09-26 criteria provided, single submitter clinical testing Variant summary: SPG11 c.1478_1482delTGTTT (p.Leu493TrpfsX63) 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. The variant allele was found at a frequency of 8e-06 in 251204 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1478_1482delTGTTT in individuals affected with Hereditary Spastic Paraplegia, Type 11 and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV003413639 SCV004114113 likely pathogenic SPG11-related disorder 2023-08-08 criteria provided, single submitter clinical testing The SPG11 c.1478_1482del5 variant is predicted to result in a frameshift and premature protein termination (p.Leu493Trpfs*63). This variant has been reported in an individual with spastic paraplegia (Haj Salem et al. 2021. PubMed ID: 33397523). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-44941183-CAAACA-C). Frameshift variants in SPG11 are expected to be pathogenic. This variant is interpreted as likely pathogenic.

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