ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.9610G>A (p.Asp3204Asn) (rs151050583)

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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 RCV000725587 SCV000337942 uncertain significance not provided 2016-07-21 criteria provided, single submitter clinical testing
GeneDx RCV000725587 SCV000590326 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing The D3204N variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The D3204N variant is observed in 3/4788 (0.06%) alleles from individuals of African background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved. Additionally, most of the reported pathogenic variants in the PLEC gene are truncating/loss-of-function. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Invitae RCV000530421 SCV000650476 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 2017-06-27 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 3204 of the PLEC protein (p.Asp3204Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs151050583, ExAC 0.06%). This variant has not been reported in the literature in individuals with a PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 285079). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The asparagine 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, this variant has uncertain impact on PLEC function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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