Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000530324 | SCV000660355 | 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 | 2023-12-12 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 773 of the PLEC protein (p.Arg773Cys). This variant is present in population databases (rs782156696, gnomAD 0.01%). This missense change has been observed in individual(s) with muscle weakness (Invitae). ClinVar contains an entry for this variant (Variation ID: 478592). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. 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. |
| Eurofins Ntd Llc |
RCV000727769 | SCV000855159 | uncertain significance | not provided | 2018-07-10 | criteria provided, single submitter | clinical testing | |
| Revvity Omics, |
RCV000727769 | SCV003817388 | uncertain significance | not provided | 2022-09-13 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV000727769 | SCV001554216 | uncertain significance | not provided | no assertion criteria provided | clinical testing | The PLEC p.Arg773Cys variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs782156696) and ClinVar (classified as a VUS by EGL Genetic Diagnostics and Invitae). The variant was identified in control databases in 19 of 254526 chromosomes at a frequency of 0.000075 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 17 of 115540 chromosomes (freq: 0.000147), African in 1 of 21574 chromosomes (freq: 0.000046) and South Asian in 1 of 27732 chromosomes (freq: 0.000036), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), and Other populations. The p.Arg773 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |