ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.1033G>C (p.Ala345Pro)

dbSNP: rs368373840
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000501596 SCV000597233 likely pathogenic Hereditary spastic paraplegia 7 2016-12-23 criteria provided, single submitter clinical testing
Paris Brain Institute, Inserm - ICM RCV000501596 SCV001451040 pathogenic Hereditary spastic paraplegia 7 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001662499 SCV001879859 uncertain significance not provided 2020-10-28 criteria provided, single submitter clinical testing
Invitae RCV000501596 SCV002306598 uncertain significance Hereditary spastic paraplegia 7 2021-08-31 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 345 of the SPG7 protein (p.Ala345Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of SPG7-related conditions (PMID: 29915382). ClinVar contains an entry for this variant (Variation ID: 436844). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPG7 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003235255 SCV003934860 uncertain significance not specified 2023-05-15 criteria provided, single submitter clinical testing Variant summary: SPG7 c.1033G>C (p.Ala345Pro) results in a non-conservative amino acid change located in the AAA+ ATPase domain (IPR003593) 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 250854 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1033G>C has been reported in the literature in at least one compound heterozygous individual affected with Hereditary Spastic Paraplegia (e.g., Sun_2019). 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 have been ascertained in the context of this evaluation (PMID: 29915382). Three ClinVar submitters (evaluation after 2014) have cited the variant with conflicting assessments, classifying the variant as VUS (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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