Submissions for variant NM_201384.3(PLEC):c.5917C>T (p.Arg1973Trp)

gnomAD frequency: 0.00001  dbSNP: rs80338756

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519116	SCV000617259	pathogenic	not provided	2022-12-12	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that the R2000W variant renders the PLEC protein's coiled-coil domain vulnerable to cleavage by calpains and other proteases in the epidermis; treatment with calpain inhibitors resulted in increased PLEC protein levels (Walko et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); Missense variant in a gene in which most reported pathogenic variants are truncating/loss of function; This variant is associated with the following publications: (PMID: 22854623, 23774525, 31001817, 11851880, 22144912, 29453417, 22864774)
Biomedical Innovation Departament, CIEMAT	RCV001352838	SCV001547431	pathogenic	Simplex epidermolysis bullosa_Ogna type	2016-03-21	criteria provided, single submitter	research
Invitae	RCV001381863	SCV001580428	pathogenic	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	2023-01-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 8262). This variant is also known as R2110W. This missense change has been observed in individuals with clinical features of autosomal dominant epidermolysis bullosa (PMID: 11851880, 22854623, 29453417). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2000 of the PLEC protein (p.Arg2000Trp).
3billion	RCV000008751	SCV004013757	pathogenic	Epidermolysis bullosa simplex, Ogna type		criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.69; 3Cnet: 0.01). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000008262 / PMID: 11851880). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 11851880, 22854623, 29453417). The variant has been reported to co-segregate with the disease in at least 7 similarly affected relatives/individuals in at least two unrelated families (PMID: 11851880, 22854623). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000008751	SCV000028960	pathogenic	Epidermolysis bullosa simplex, Ogna type	2002-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000008751	SCV000041740	not provided	Epidermolysis bullosa simplex, Ogna type		no assertion provided	literature only