ClinVar Miner

Submissions for variant NM_003119.4(SPG7):c.2228T>C (p.Ile743Thr) (rs752623413)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000198819 SCV000252332 likely pathogenic not provided 2017-12-26 criteria provided, single submitter clinical testing The I743T variant in the SPG7 gene has been reported previously in the compound heterozygous state in multiple individuals with ataxia, upper motor neuron syndrome, and progressive external ophthalmoplegia (Brugman et al., 2008; van Gassen et al., 2012; Pfeffer et al., 2014; Pfeffer et al., 2015). One of these patients presented with gait imbalance and dysarthria (Pfeffer et al., 2015). The I743T variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The I743T variant is a non-conservative amino acid substitution, which occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (E741K, D742N, I747T) have been reported in the Human Gene Mutation Database in association with SPG7-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The I743T variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.
Genetic Services Laboratory, University of Chicago RCV000500664 SCV000597238 pathogenic Spastic paraplegia 7 2017-05-17 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000500664 SCV000607223 not provided Spastic paraplegia 7 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000500664 SCV000762593 pathogenic Spastic paraplegia 7 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 743 of the SPG7 protein (p.Ile743Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs752623413, ExAC 0.01%). This variant has been reported to segregate with autosomal recessive primary lateral sclerosis and hereditary spastic paraplegia in families (PMID: 27123479, 22964162). It has also been reported in the compound heterozygous state in individuals affected with adult-onset upper motor neuron syndrome, ataxia, or progressive external ophthalmoplegia (PMID: 18799786, 25681447, 24727571). ClinVar contains an entry for this variant (Variation ID: 215218). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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