ClinVar Miner

Submissions for variant NM_182961.4(SYNE1):c.8311G>A (p.Val2771Ile) (rs374862218)

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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 RCV000725070 SCV000333733 uncertain significance not provided 2015-09-03 criteria provided, single submitter clinical testing
GeneDx RCV000725070 SCV000620172 uncertain significance not provided 2018-12-20 criteria provided, single submitter clinical testing The V2778I variant in the SYNE1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The V2778I variant is observed in 5/10406 (0.048%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016). The V2778I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret V2778I as a variant of uncertain significance.
Invitae RCV000542430 SCV000649217 uncertain significance Spinocerebellar ataxia, autosomal recessive 8; Emery-Dreifuss muscular dystrophy 4, autosomal dominant 2017-10-24 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2778 of the SYNE1 protein (p.Val2778Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs374862218, ExAC 0.05%) but has not been reported in the literature in individuals with a SYNE1-related disease. ClinVar contains an entry for this variant (Variation ID: 282323). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but 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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