ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.7464G>T (p.Lys2488Asn) (rs371673069)

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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 RCV000724247 SCV000229515 uncertain significance not provided 2014-11-23 criteria provided, single submitter clinical testing
GeneDx RCV000724247 SCV000577341 uncertain significance not provided 2017-04-04 criteria provided, single submitter clinical testing The K2488N variant in the PLEC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. Although not present in the homozygous state, the K2488N variant is observed in 13/65460 (0.02%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). The K2488N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Lysine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret K2488N as a variant of uncertain significance.
Invitae RCV000705315 SCV000834305 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 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 2488 of the PLEC protein (p.Lys2488Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant is present in population databases (rs371673069, ExAC 0.02%). This variant has not been reported in the literature in individuals with PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 196751). 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 C0"). 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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