Submissions for variant NM_000094.4(COL7A1):c.7270C>T (p.Arg2424Trp)

dbSNP: rs1189942401

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biomedical Innovation Departament, CIEMAT	RCV001352858	SCV001547372	pathogenic	Epidermolysis bullosa dystrophica	2016-03-09	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV003718410	SCV004509317	pathogenic	not provided	2024-04-17	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 2424 of the COL7A1 protein (p.Arg2424Trp). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 29272047, 32484238, 34948168). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant dystrophic epidermolysis bullosa (PMID: 34046686); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 1048045). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in deletion of the last 26 amino acids of exon 94 and introduces a premature termination codon (PMID: 34948168). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004579573	SCV005062122	pathogenic	Recessive dystrophic epidermolysis bullosa	2024-03-28	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.7270C>T (p.Arg2424Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: One predicts the variant abolishes the canonical 5' splicing donor site and two predict the variant weakens the 5' donor site. Two also predict the variant creates a new 5' donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing, ultimately resulting in a frameshift and premature termination codon (Akasaka_2021). The variant allele was found at a frequency of 4.1e-06 in 241652 control chromosomes (gnomAD). c.7270C>T has been reported in the literature in the compound heterozygous state together with pathogenic variants in individuals affected with Recessive Dystrophic Epidermolysis Bullosa (e.g. Knopfel_2018, Chen_2020, Akasaka_2021). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 34948168, 32484238, 29272047). ClinVar contains an entry for this variant (Variation ID: 1048045). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005038118	SCV005664140	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	2024-03-26	criteria provided, single submitter	clinical testing