Submissions for variant NM_201384.3(PLEC):c.2237G>A (p.Arg746His)

gnomAD frequency: 0.00153  dbSNP: rs200887085

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175499	SCV000226986	likely benign	not specified	2015-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000175499	SCV000534202	likely benign	not specified	2017-10-31	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000555489	SCV000660322	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	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 773 of the PLEC protein (p.Arg773His). This variant is present in population databases (rs200887085, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of PLEC-related disorders (PMID: 26498160, 31862442). ClinVar contains an entry for this variant (Variation ID: 195001). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "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. 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.
CeGaT Center for Human Genetics Tuebingen	RCV000999100	SCV001155549	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	PLEC: BS1
Athena Diagnostics	RCV000175499	SCV001476756	likely benign	not specified	2024-04-30	criteria provided, single submitter	clinical testing