ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.4445G>A (p.Arg1482His) (rs542878693)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000523948 SCV000618938 uncertain significance not specified 2017-07-20 criteria provided, single submitter clinical testing The R1482H variant in the PLEC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1482H variant is observed in 2/4926 (0.04%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The R1482H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Arginine 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 R1482H as a variant of uncertain significance.
Invitae RCV000798395 SCV000938011 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 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 1482 of the PLEC protein (p.Arg1482His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs542878693, ExAC 0.04%). This variant has not been reported in the literature in individuals with PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 450363). 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 tolerated, 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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