Submissions for variant NM_000094.4(COL7A1):c.6187C>T (p.Arg2063Trp)

gnomAD frequency: 0.00001  dbSNP: rs121912849

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413807	SCV000490501	pathogenic	not provided	2022-11-02	criteria provided, single submitter	clinical testing	Reported previously in the homozygous state or with a second COL7A1 variant in patients with autosomal recessive DEB (Hovnanian et al., 1997; Hashimoto et al., 1999; Gardella et al., 2002; Kern et al., 2009; Ben Brick et al., 2014; Kopeckova et al., 2016; Chen et al., 2020); Identified in unrelated patients with generalized DEB as a single heterozygous variant with no second COL7A1 variant identified (Posteraro et al., 2005; Escamez et al., 2010; Ben Brick et al., 2014; Danescu et al., 2015); Published functional studies demonstrate that this variant is located next to the helical interruption hinge region and results in local triple helix destabilization, and fibroblasts with this variant exhibit decreased motility and adhesion in vitro (Woodley et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20184583, 33969388, 21448560, 12207583, 19681861, 10232406, 18558993, 16271705, 12880418, 25201089, 15115517, 18030675, 26707537, 28830826, 34426522, 24170138, 35314946, 32484238, 9326325, 18450758)
Biomedical Innovation Departament, CIEMAT	RCV001352769	SCV001547351	pathogenic	Epidermolysis bullosa dystrophica	2017-10-31	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413807	SCV001578934	pathogenic	not provided	2024-05-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2063 of the COL7A1 protein (p.Arg2063Trp). This variant is present in population databases (rs121912849, gnomAD 0.002%). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9326325, 12207583, 28830826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 17456). 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 expected to disrupt COL7A1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects COL7A1 function (PMID: 18450758). For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000019007	SCV002073249	pathogenic	Recessive dystrophic epidermolysis bullosa		criteria provided, single submitter	clinical testing	The missense variant p.R2063W in COL7A1 (NM_000094.3) has been previously reported in affected patients (Ben Brick et al., 2014).Functional studies have demonstrated a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.R2063W variant is observed in 2/1,13,580 (0.0018%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000019007	SCV005203708	pathogenic	Recessive dystrophic epidermolysis bullosa	2024-07-03	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.6187C>T (p.Arg2063Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251234 control chromosomes. c.6187C>T has been reported in the literature in the presumed compound heterozygous, compound heterozygous, or homozygous state in multiple individuals affected with autosomal recessive Dystrophic Epidermolysis Bullosa (example, Ben Brick_2014, Chen_2023, Hovanian_1997, Jerabkova_2010), including in at least 1 individual who carried a pathogenic variant in trans. Additionally, this variant was found in the heterozygous state in several individuals affected with dystrophic epidermolysis bullosa (example, Ben Brick_2014, Cuadro-Corrales_2010, Danescu_2015, Escamez_2010, Posteraro_2005), however parental genotype/phenotype correlations were not available. These data indicate that the variant is very likely to be associated with disease. In homozygous patient samples, this variant was associated with normal transcription and protein expression levels in at least 1 study (example, Hovanian_1997), however follow up studies in patient samples heterozygous for this variant found that collagen VII protein levels were reduced and altered (data not quantified) (example, Escamez_2010, Posteraro_2005). In vitro, this variant resulted in reduced fibroblast adhesion and keratinocyte migration, as well as increased susceptibility to protease digestion (example, Woodley_2008, Woodley_2021). The following publications have been ascertained in the context of this evaluation (PMID: 24170138, 36287101, 20920254, 25201089, 20184583, 9326325, 20598510, 16271705, 27899325, 18450758, 34674926). ClinVar contains an entry for this variant (Variation ID: 17456). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000019007	SCV000039294	pathogenic	Recessive dystrophic epidermolysis bullosa	2008-02-01	no assertion criteria provided	literature only