ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.10825G>A (p.Gly3609Ser) (rs202010719)

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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 RCV000723631 SCV000229596 uncertain significance not provided 2017-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000723631 SCV000617932 uncertain significance not provided 2015-11-24 criteria provided, single submitter clinical testing The G3609S variant in the PLEC gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The G3609S variant was not observed with any significant frequency in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G3609S 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. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret G3609S as a variant of uncertain significance.
Invitae RCV000534001 SCV000660328 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 2016-12-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 3609 of the PLEC protein (p.Gly3609Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs202010719, ExAC 0.08%) but has not been reported in the literature in individuals with a PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 196813). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). The serine 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. In summary, this variant is a rare missense change with uncertain impact on protein function. Because it is found in the population at an appreciable frequency, this variant is not anticipated to cause disease. However, the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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