ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.1834G>A (p.Ala612Thr) (rs368520468)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000497554 SCV000590147 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing The A612T variant in the PLEC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A612T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A612T 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 in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A612T as a variant of uncertain significance.
Invitae RCV000692355 SCV000820173 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 2018-03-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 612 of the PLEC protein (p.Ala612Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 432425). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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