Submissions for variant NM_201384.3(PLEC):c.8548A>G (p.Thr2850Ala)

gnomAD frequency: 0.00001  dbSNP: rs782009185

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001372135	SCV001568740	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	2018-07-09	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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine 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. This variant has not been reported in the literature in individuals with PLEC-related disease. This variant is present in population databases (rs782009185, ExAC 0.003%). This sequence change replaces threonine with alanine at codon 2877 of the PLEC protein (p.Thr2877Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine.
Neuberg Centre For Genomic Medicine, NCGM	RCV004771501	SCV005382465	uncertain significance	Epidermolysis bullosa simplex 5C, with pyloric atresia	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.8548A>G(p.Thr2850Ala) in PLEC gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.8548A>G variant has 0.001% allele frequency in gnomAD Exomes. This variant has been submitted to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment.The amino acid Threonine at position 2850 is changed to a Alanine changing protein sequence and it might alter its composition and physico-chemical properties.Computational evidence (Polyphen-Benign, SIFT-damaging and Mutation Taster-disease causing) predicts conflicting evidence on protein structure and function for this variant. The reference amino acid p.Thr2850Ala in PLEC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.