ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.5074G>A (p.Val1692Ile)

gnomAD frequency: 0.00002  dbSNP: rs764497276
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000642577 SCV000764264 uncertain significance Hereditary spastic paraplegia 11 2022-09-14 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1692 of the SPG11 protein (p.Val1692Ile). This variant is present in population databases (rs764497276, gnomAD 0.003%). 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: 534880). 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 SPG11 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.
GeneDx RCV004721515 SCV005327667 uncertain significance not provided 2023-12-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in patient with clinical diagnosis of blindness; however, no additional information was provided (PMID: 32483926); This variant is associated with the following publications: (PMID: 32483926)
PreventionGenetics, part of Exact Sciences RCV004748878 SCV005357538 uncertain significance SPG11-related disorder 2024-06-08 no assertion criteria provided clinical testing The SPG11 c.5074G>A variant is predicted to result in the amino acid substitution p.Val1692Ile. This variant was reported in an individual with retinal or optic nerve disease; however, no additional information was provided to support pathogenicity (supplementary data, Diñeiro et al 2020. PubMed ID: 32483926). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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