Submissions for variant NM_201384.3(PLEC):c.11438G>A (p.Arg3813His)

gnomAD frequency: 0.00005  dbSNP: rs782311906

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000441095	SCV000517450	likely benign	not specified	2015-06-04	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000793945	SCV000933325	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	2023-07-20	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: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 379928). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. This variant is present in population databases (rs782311906, gnomAD 0.03%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 3840 of the PLEC protein (p.Arg3840His).
Illumina Laboratory Services, Illumina	RCV001270892	SCV001451673	uncertain significance	PLEC-related epidermolysis bullosa	2020-08-03	criteria provided, single submitter	clinical testing	The PLEC c.11519G>A (p.Arg3840His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is found at a frequency of 0.0003260 in the African population of the Genome Aggregation Database. To date, only null variants have been reported in association with autosomal recessive forms of the disease (Pfender et al. 2005). Based on the limited evidence, the p.Arg3840His variant is classified as a variant of uncertain significance for PLEC-related epidermolysis bullosa.
Illumina Laboratory Services, Illumina	RCV003985085	SCV004801463	uncertain significance	Epidermolysis bullosa simplex, Ogna type	2020-08-03	criteria provided, single submitter	clinical testing	The PLEC c.11519G>A p.(Arg3840His) variant is a missense variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is found at a frequency of 0.0003260 in the African population of the Genome Aggregation Database (version 2.1.1). To date, only null variants have been reported in association with autosomal recessive forms of the disease (Pfender et al. 2005). Based on the limited evidence, the c.11519G>A p.(Arg3840His) variant is classified as a variant of uncertain significance for epidermolysis bullosa simplex.