ClinVar Miner

Submissions for variant NM_201384.3(PLEC):c.3973G>A (p.Glu1325Lys)

gnomAD frequency: 0.00001  dbSNP: rs782178037
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000690753 SCV000818455 uncertain significance Epidermolysis bullosa simplex 5B, with muscular dystrophy; Epidermolysis bullosa simplex, Ogna type; Epidermolysis bullosa simplex 5C, with pyloric atresia; Autosomal recessive limb-girdle muscular dystrophy type 2Q; Epidermolysis bullosa simplex with nail dystrophy 2019-12-13 criteria provided, single submitter clinical testing 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. 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: "Possibly Damaging "; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with PLEC-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 1352 of the PLEC protein (p.Glu1352Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine.
Clinical Genomics Laboratory, Washington University in St. Louis RCV003458504 SCV004177178 uncertain significance Epidermolysis bullosa simplex 5B, with muscular dystrophy; Epidermolysis bullosa simplex 5C, with pyloric atresia; Autosomal recessive limb-girdle muscular dystrophy type 2Q 2023-08-14 criteria provided, single submitter clinical testing The PLEC c.3973G>A (p.Glu1325Lys) variant, to our knowledge, has not been reported in the medical literature but has been reported in the ClinVar database as a germline variant of uncertain significance by one submitter. This variant is only observed on 4/248,810 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. The amino acid at this position occurs in exon 30 and computational predictors indicate that the variant is damaging, evidence that correlates with impact to plectin function. Due to limited information, and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.

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