ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.11081G>T (p.Arg3694Leu) (rs369798520)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000727000 SCV000618233 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing The R3694L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R3694L variant is observed in 28/23,850 (0.12%) alleles from individuals of African background (Lek et al., 2016). Most reported pathogenic variants in the PLEC gene are truncating/loss-of-function. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated across species. However, 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. In silico analysis predicts this variant is probably damaging to the protein structure/function.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000727000 SCV000704826 uncertain significance not provided 2017-01-04 criteria provided, single submitter clinical testing
Invitae RCV000648528 SCV000770348 uncertain significance Epidermolysa bullosa simplex and limb girdle muscular dystrophy; Epidermolysis bullosa simplex, Ogna type; Epidermolysis bullosa simplex with pyloric atresia; Limb-girdle muscular dystrophy, type 2Q; Epidermolysis bullosa simplex with nail dystrophy 2018-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 3694 of the PLEC protein (p.Arg3694Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs369798520, ExAC 0.1%). This variant has not been reported in the literature in individuals with PLEC-related disease. 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 disruptive, 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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