ClinVar Miner

Submissions for variant NM_001130987.2(DYSF):c.2707G>A (p.Glu903Lys) (rs770997582)

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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 RCV000725888 SCV000340257 uncertain significance not provided 2017-01-03 criteria provided, single submitter clinical testing
GeneDx RCV000725888 SCV000618695 uncertain significance not provided 2017-06-28 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the DYSF gene. The E885K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E885K variant is observed in 2/16512 (0.01%) alleles from individuals of South Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E885K 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. However, 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. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000821051 SCV000961792 uncertain significance Dysferlinopathy 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 885 of the DYSF protein (p.Glu885Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs770997582, ExAC 0.01%). This variant has not been reported in the literature in individuals with DYSF-related disease. ClinVar contains an entry for this variant (Variation ID: 286711). 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 and their clinical significance is uncertain. 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.

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