ClinVar Miner

Submissions for variant NM_000445.5(PLEC):c.7903G>A (p.Ala2635Thr) (rs199995144)

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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 RCV000724784 SCV000229647 uncertain significance not provided 2015-05-05 criteria provided, single submitter clinical testing
GeneDx RCV000724784 SCV000582522 uncertain significance not provided 2017-05-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the PLEC gene. The A2635T variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The A2635T variant is observed in 4/7806 (0.05%) alleles from individuals of East Asian background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A2635T 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. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae RCV000816099 SCV000956589 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 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 2635 of the PLEC protein (p.Ala2635Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs199995144, ExAC 0.05%). This variant has not been reported in the literature in individuals with PLEC-related disease. ClinVar contains an entry for this variant (Variation ID: 196858). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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