ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.24881A>G (p.Asp8294Gly) (rs138407813)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000725092 SCV000333947 uncertain significance not provided 2018-02-09 criteria provided, single submitter clinical testing
GeneDx RCV000725092 SCV000621142 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing The D8223G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D8223G variant is observed in 57/24,030 (0.24%) alleles from individuals of African background (Lek et al., 2016). This 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. This substitution occurs at a position that is conserved in mammals; however, missense variants in nearby residues have not been reported in the Human Gene Mutation Database in association with SYNE1-related disorders (Stenson et al., 2014). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000543385 SCV000649143 uncertain significance Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2017-06-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 8223 of the SYNE1 protein (p.Asp8223Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs138407813, ExAC 0.2%). This variant has not been reported in the literature in individuals with a SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 282456). 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on SYNE1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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