ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.6545C>T (p.Ala2182Val) (rs201922111)

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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 RCV000727788 SCV000855189 uncertain significance not provided 2018-03-15 criteria provided, single submitter clinical testing
GeneDx RCV000497742 SCV000590631 uncertain significance not specified 2017-06-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEC gene. The A2182V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A2182V variant is observed in 13/15728 (0.08%) alleles from individuals of South Asian background, in the ExAC data set (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position conserved in mammals. However, the A2182V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000648566 SCV000770386 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 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 2182 of the PLEC protein (p.Ala2182Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs201922111, ExAC 0.08%). This variant has not been reported in the literature in individuals with PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 432861). 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: "Benign"; Align-GVGD: "Class C0"). 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, 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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