ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.1492C>T (p.Gln498Ter)

gnomAD frequency: 0.00001  dbSNP: rs312262728
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV001092499 SCV001249038 pathogenic not provided 2018-01-01 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000034301 SCV001810226 pathogenic Hereditary spastic paraplegia 11 2021-07-22 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000034301 SCV003761348 pathogenic Hereditary spastic paraplegia 11 2023-01-25 criteria provided, single submitter curation The homozygous p.Gln498Ter variant in SPG11 was identified by our study in two siblings with spastic paraplegia. The p.Gln498Ter variant in SPG11 has been reported in 2 unrelated individuals with hereditary spastic paraplegia 11 (PMID: 20971220, PMID: 24833714) and segregated with disease in five affected relatives from one family (PMID: 20971220), but has been identified in 0.002% (2/113568) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs312262728). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. Of these 2 unrelated affected individuals (PMID: 20971220, PMID: 24833714), one was a homozygote (PMID: 20971220) and one was a compound heterozygote who carried a likely pathogenic variant in trans (PMID: 24833714, ClinVar Variation ID: 1180685), which increases the likelihood that the p.Gln498Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 41399) and has been interpreted as pathogenic by the Genome-Nilou Lab, the ‚Äã‚ÄãCeGaT Center for Human Genetics Tuebingen, and GeneReviews. This nonsense variant leads to a premature termination codon at position 498, which is predicted to lead to a truncated or absent protein. Loss of function of the SPG11 gene is an established disease mechanism in autosomal recessive SPG11-related neurologic disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive spastic paraplegia 11. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_Strong, PP1_Moderate (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp RCV000034301 SCV004296964 pathogenic Hereditary spastic paraplegia 11 2024-02-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln498*) 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 (rs312262728, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 20971220, 24833714). ClinVar contains an entry for this variant (Variation ID: 41399). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000034301 SCV000058251 pathologic Hereditary spastic paraplegia 11 2013-01-31 no assertion criteria provided curation Converted during submission to Pathogenic.

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