Submissions for variant NM_201384.3(PLEC):c.5390G>A (p.Arg1797His)

gnomAD frequency: 0.00019  dbSNP: rs782581787

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724830	SCV000229479	uncertain significance	not provided	2015-05-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000724830	SCV000618148	uncertain significance	not provided	2018-01-29	criteria provided, single submitter	clinical testing	The R1824H variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1824H variant is observed in 17/68,386 (0.03%) alleles from individuals of European background (Lek et al., 2016). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In addition, most reported pathogenic variants in the PLEC gene are truncating/loss-of-function. However, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000525521	SCV000650318	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	2024-01-08	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 1824 of the PLEC protein (p.Arg1824His). This variant is present in population databases (rs782581787, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with PLEC-related conditions. ClinVar contains an entry for this variant (Variation ID: 196720). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLEC protein function with a negative predictive value of 80%. 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.
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000785604	SCV000924183	uncertain significance	Arrhythmogenic right ventricular dysplasia 1		criteria provided, single submitter	research
Revvity Omics, Revvity	RCV000724830	SCV003814948	uncertain significance	not provided	2021-10-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004737271	SCV005350885	uncertain significance	PLEC-related disorder	2024-06-26	no assertion criteria provided	clinical testing	The PLEC c.5471G>A variant is predicted to result in the amino acid substitution p.Arg1824His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.