ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.5414G>A (p.Arg1805His)

gnomAD frequency: 0.00003  dbSNP: rs775768037
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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 RCV000553692 SCV000642250 uncertain significance Hereditary spastic paraplegia 11 2022-08-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1805 of the SPG11 protein (p.Arg1805His). This variant is present in population databases (rs775768037, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SPG11-related conditions. ClinVar contains an entry for this variant (Variation ID: 466539). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV004782438 SCV005395610 uncertain significance not specified 2024-09-06 criteria provided, single submitter clinical testing Variant summary: SPG11 c.5414G>A (p.Arg1805His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5414G>A has been reported in a cohort of individuals affected with amyotrophic lateral sclerosis (e.g., Grassano_2022). However, these report(s) do not provide unequivocal conclusions about association of the variant with SPG11-related conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 35896380). ClinVar contains an entry for this variant (Variation ID: 466539). Based on the evidence outlined above, the variant was classified as uncertain significance.

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