ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.12106C>T (p.Arg4036Cys) (rs989279969)

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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 RCV000726512 SCV000701541 uncertain significance not provided 2016-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000726512 SCV000620723 uncertain significance not provided 2017-09-13 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEC gene. The R4036C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R4036C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R4036C 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, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000560558 SCV000650162 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 2017-06-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 4036 of the PLEC protein (p.Arg4036Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). 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 (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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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