ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.6428A>C (p.His2143Pro)

gnomAD frequency: 0.00001  dbSNP: rs1490278448
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000817786 SCV000958369 uncertain significance Hereditary spastic paraplegia 11 2018-10-06 criteria provided, single submitter clinical testing This sequence change replaces histidine with proline at codon 2143 of the SPG11 protein (p.His2143Pro). The histidine residue is weakly conserved and there is a moderate physicochemical difference between histidine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SPG11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000817786 SCV002767621 uncertain significance Hereditary spastic paraplegia 11 2020-05-25 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_025137.3(SPG11):c.6428A>C in exon 34 of 40 of the SPG11 gene. This substitution is predicted to create a moderate amino acid change from a histidine to a proline at position 2143 of the protein; NP_079413.3(SPG11):p.(His2143Pro). The histidine at this position has low conservation (100 vertebrates, UCSC), and is located within the spatacsin C-terminal domain (NCBI, PDB, Decipher). In silico software predictions of the pathogenicity of this variant are conflicting (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a global population frequency of 0.0008% (2 heterozygotes, 0 homozygotes) with a European sub-population frequency of 0.002%. This variant has been previously reported as a VUS in ClinVar. Based on information available at the time of curation, this variant has been classified as a VUS.

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