Submissions for variant NM_000094.4(COL7A1):c.5820G>A (p.Pro1940=)

gnomAD frequency: 0.00010  dbSNP: rs200972872

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497540	SCV000589317	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing	RNA studies demonstrate that the variant reduces the quality of the splice donor site in intron 70, causing abnormal gene splicing and exon skipping of exon 70, in approximately 40% of transcripts (PMID: 9804332); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33969388, 9804332, 21448560, 12485454, 31589614, 34426522, 31001817, 31930626, 33274474)
Fulgent Genetics, Fulgent Genetics	RCV000763114	SCV000893656	likely pathogenic	Recessive dystrophic epidermolysis bullosa; Pretibial dystrophic epidermolysis bullosa; Dominant dystrophic epidermolysis bullosa with absence of skin; Transient bullous dermolysis of the newborn; Epidermolysis bullosa pruriginosa; Nonsyndromic congenital nail disorder 8; Generalized dominant dystrophic epidermolysis bullosa	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000497540	SCV000934821	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change affects codon 1940 of the COL7A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL7A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs200972872, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9804332, 31001817, 31930626). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431810). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 70, but is expected to preserve the integrity of the reading-frame (PMID: 9804332). This variant disrupts the triple helix domain of COL7A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and variants at these glycine residues in COL7A1 are more frequently observed in individuals with disease than in the general population (PMID: 22058051). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. For these reasons, this variant has been classified as Pathogenic.
Biomedical Innovation Departament, CIEMAT	RCV001148931	SCV001547333	pathogenic	Epidermolysis bullosa dystrophica	2018-11-26	criteria provided, single submitter	research
Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires	RCV002279273	SCV002499346	pathogenic	Recessive dystrophic epidermolysis bullosa	2022-03-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004535558	SCV004241029	pathogenic	COL7A1-related disorder	2023-12-13	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.5820G>A (p.Pro1940Pro) results in a synonymous change to the encoded protein sequence and also alters the last nucleotide of Exon 71 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, and two predict the variant weakens the same 5' donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, leading to both exon skipping and intron retention (e.g., Terracina_1998, Vahidnezhad_2020). The variant allele was found at a frequency of 8.8e-05 in 250822 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5820G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (e.g., Terracina_1998, Gardella_2002, Vahidnezhad_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating the impact of the variant, finding markedly reduced COL7A1 transcript levels in a whole-skin biopsy from a homozgyous patient (e.g., Vahidnezhad_2020). The following publications have been ascertained in the context of this evaluation (PMID: 12485454, 9804332, 31930626). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 5; likely pathogenic, n = 1; VUS, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000018979	SCV000039266	pathogenic	Epidermolysis bullosa dystrophica, autosomal recessive, localisata variant	1998-11-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001272350	SCV001454262	pathogenic	Epidermolysis bullosa dystrophica inversa, autosomal recessive	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535558	SCV005360284	pathogenic	COL7A1-related disorder	2024-09-24	no assertion criteria provided	clinical testing	The COL7A1 c.5820G>A variant is not predicted to result in an amino acid change (p.=). This variant leads to skipping of exon 70 of the COL7A1 gene (Terracina et al. 1998. PubMed ID: 9804332). This variant has been reported in the compound heterozygous state in an individual with a mild form of dystrophic epidermolysis bullosa (Terracina et al. 1998. PubMed ID: 9804332; Supplementary Table SII, Almaani et al. 2011. PubMed ID: 21448560; Mariath et al. 2019. PubMed ID: 31001817). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.