ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.4432G>A (p.Glu1478Lys) (rs868906137)

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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 RCV000725142 SCV000334418 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000338251 SCV000577413 uncertain significance not specified 2017-03-30 criteria provided, single submitter clinical testing The E1478K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E1478K variant is observed in 35/30816 (0.11%) alleles from individuals of European 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 across species; 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 RCV000534113 SCV000650276 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 2018-08-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1478 of the PLEC protein (p.Glu1478Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs868906137, ExAC 0.1%). This variant has not been reported in the literature in individuals with a PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 282780). 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: "Probably Damaging"; Align-GVGD: "Class C55"). In summary, this variant has uncertain impact on PLEC 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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