ClinVar Miner

Submissions for variant NM_025137.4(SPG11):c.2075T>C (p.Ile692Thr)

gnomAD frequency: 0.00013  dbSNP: rs144012151
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000487663 SCV000575005 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing SPG11: PM2
Labcorp Genetics (formerly Invitae), Labcorp RCV000642578 SCV000764265 uncertain significance Hereditary spastic paraplegia 11 2022-07-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 692 of the SPG11 protein (p.Ile692Thr). This variant is present in population databases (rs144012151, gnomAD 0.02%). 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: 425067). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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 RCV000487663 SCV002571293 uncertain significance not provided 2022-03-11 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26556829)
Ambry Genetics RCV002420247 SCV002729814 uncertain significance Inborn genetic diseases 2020-09-14 criteria provided, single submitter clinical testing The p.I692T variant (also known as c.2075T>C), located in coding exon 11 of the SPG11 gene, results from a T to C substitution at nucleotide position 2075. The isoleucine at codon 692 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab RCV002467836 SCV002764083 uncertain significance Amyotrophic lateral sclerosis type 5 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002467837 SCV002764085 uncertain significance Charcot-Marie-Tooth disease axonal type 2X criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000642578 SCV002764086 uncertain significance Hereditary spastic paraplegia 11 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000642578 SCV004047842 uncertain significance Hereditary spastic paraplegia 11 criteria provided, single submitter clinical testing The c.2075T>C (p.Ile692Thr) missense variant in SPG11 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency (0.01%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as a Variant of Uncertain Significance. The amino acid Ile at position 692 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile692Thr in SPG11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
Mayo Clinic Laboratories, Mayo Clinic RCV000487663 SCV005409924 uncertain significance not provided 2024-03-15 criteria provided, single submitter clinical testing

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