ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.1730G>A (p.Gly577Asp)

gnomAD frequency: 0.00001  dbSNP: rs1329063851
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Paris Brain Institute, Inserm - ICM RCV001391527 SCV001451060 pathogenic Hereditary spastic paraplegia 7 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001819969 SCV002064533 likely pathogenic not provided 2021-06-18 criteria provided, single submitter clinical testing DNA sequence analysis of the SPG7 gene demonstrated a sequence change,c.1730G>A, in exon 13 that results in an amino acid change, p.Gly577Asp. This sequence change is absent in the gnomAD population database. The p.Gly577Asp change has been previously described in the compound heterozygous state in one individual with spastic paraplegia (PMID: 21623769). Another different sequence change affecting the same amino acid (p.Gly577Ser) has also been reported in the compound heterozygous state in one individual with spastic paraplegia (PMID: 14985266). The p.Gly577Asp change affects a highly conserved amino acid residue located in the zinc binding motif of the SPG7 protein. The p.Gly577Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Overall, this evidence suggests p.Gly577Asp is likely pathogenic, however functional studies have not been performed to prove this conclusively.
Revvity Omics, Revvity RCV001391527 SCV003820053 uncertain significance Hereditary spastic paraplegia 7 2021-01-14 criteria provided, single submitter clinical testing
PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research RCV001391527 SCV005044657 pathogenic Hereditary spastic paraplegia 7 2022-01-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV004690042 SCV005184721 uncertain significance not specified 2024-05-14 criteria provided, single submitter clinical testing Variant summary: SPG7 c.1730G>A (p.Gly577Asp) results in a non-conservative amino acid change located in the Peptidase M41 domain (IPR000642) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1730G>A has been reported in the literature in an individual affected with Hereditary Spastic Paraplegia 7 (Schlipf_2011). 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 publications have been ascertained in the context of this evaluation (PMID: 21623769). ClinVar contains an entry for this variant (Variation ID: 989129). Based on the evidence outlined above, the variant was classified as uncertain significance.

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