ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1735A>C (p.Asn579His) (rs144594804)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000658865 SCV000780662 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000658865 SCV000565590 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing The N579H variant has been previously reported in an individual with an apparently sporadic, adult-onset upper motor neuron syndrome (Brugman et al., 2005). The N579H variant has also been reported previously in two individuals with hereditary spastic paraplegia who harbor a second SPAST variant; however, phase is unknown as parental testing was not performed (Chelban et al., 2017; Depienne et al., 2006). The N579H variant is observed in 89/126190 (0.01%) alleles from individuals of European Non-Finnish background (Lek et al., 2016). The N579H variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This substitution alters a conserved position in the AAA domain of the SPAST protein, which has been demonstrated to be an important functional domain for microtubule disassembly (Errico et al., 2002; Blackstone et al., 2011; Solowska et al., 2015).
Genetic Services Laboratory, University of Chicago RCV000193599 SCV000249012 uncertain significance not specified 2014-06-27 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000509114 SCV000607201 not provided Spastic paraplegia 4, autosomal dominant 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.
GenomeConnect, ClinGen RCV000658865 SCV000986750 not provided not provided no assertion provided phenotyping only Variant interpretted as not providedand reported on 04/10/2018 by GTR ID 26957. 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 RCV000509114 SCV000645354 uncertain significance Spastic paraplegia 4, autosomal dominant 2017-10-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 579 of the SPAST protein (p.Asn579His). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs144594804, ExAC 0.08%). This variant has been reported in 3 individuals affected with hereditary or sporadic spastic paraplegia (PMID: 16240363, 17594340, 16055926, 28572275). ClinVar contains an entry for this variant (Variation ID: 212290). This variant occurs with a pathogenic variant in SPAST in one individual (Invitae). While it is unknown if these variants are on the same or opposite chromosomes, this observation suggests that the c.1735A>C variant is not a primary cause of disease. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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