ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.9304C>T (p.Arg3102Trp) (rs376638828)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000493669 SCV000581765 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing The R3102W variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R3102W variant is observed in 4/8340 (0.05%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). 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 PLEC-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 RCV000550224 SCV000650466 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 2018-05-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 3102 of the PLEC protein (p.Arg3102Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs376638828, ExAC 0.05%). This variant has not been reported in the literature in individuals with PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 429245). 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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