ClinVar Miner

Submissions for variant NM_014946.3(SPAST):c.1625A>G (p.Asp542Gly) (rs142053576)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UCLA Clinical Genomics Center, UCLA RCV000199081 SCV000255472 likely pathogenic Spastic paraplegia 4, autosomal dominant 2013-06-25 criteria provided, single submitter clinical testing
GeneDx RCV000486146 SCV000565589 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing The D542G variant has previously been reported in several unrelated individuals with a variety of phenotypes including sporadic and hereditary spastic paraplegia, upper motor neuron syndrome, and in patients suspected of having a mitochondrial disorder, although segregation analysis was not performed for any of these individuals and most individuals did not have comprehensive genetic analysis for other genes associated with hereditary spastic paraplegia (Brugman et al., 2005; Orlacchio et al., 2008; de Bot et al., 2010; DaRe et al., 2013; Lee et al., 2014). The D542G variant is observed in 7/10078 (0.07%) alleles from individuals of Latino background in the ExAC dataset (Lek et al., 2016). The D542G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Although this substitution occurs at a position that is not highly conserved it occurs within the AAA domain of the SPAST protein, which has been demonstrated to be an important functional domain for microtubule disassembly, and in silico analysis predicts this variant is probably damaging to the protein structure/function (Brugman et al., 2005; Blackstone et al., 2011). In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Mendelics RCV000199081 SCV001135659 uncertain significance Spastic paraplegia 4, autosomal dominant 2019-05-28 criteria provided, single submitter clinical testing

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