ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.4936G>A (p.Glu1646Lys) (rs782026068)

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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 RCV000725097 SCV000333994 uncertain significance not provided 2015-09-08 criteria provided, single submitter clinical testing
GeneDx RCV000321459 SCV000572999 uncertain significance not specified 2017-02-10 criteria provided, single submitter clinical testing The E1646K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The E1646K variant is not observed at a significant frequency in large population cohorts (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. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000527679 SCV000650301 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 2018-09-14 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1646 of the PLEC protein (p.Glu1646Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. While this variant is present in population databases (rs782026068), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a PLEC-related disease. 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: "Unknown"; Align-GVGD: "Class C55"). In summary, this variant is a rare missense change with uncertain impact on 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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