Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Molecular Genetics, |
RCV002225232 | SCV002503827 | likely pathogenic | Generalized dominant dystrophic epidermolysis bullosa | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace glycine with valine at codon 1913 of the COL7A1 protein (p.Gly1913Val). The glycine residue is highly conserved in mammals and many birds and sarcopterygii (100 vertebrates, UCSC with incomplete alignment data in some species), and is located within the collagenous triple-helix domain in a Gly-X-Y motif; glycine substitutions within this functional domain have a well-established pathogenic dominant-negative effect (PM1). There is a large physicochemical difference between glycine and valine. The variant is absent in a large population cohort (PM2; gnomAD v2.1 and v3) and has not been previously reported in the literature. A proband with a phenotype specific for dystrophic epidermolysis bullosa (DEB) with a dominant family history (PS4_Supporting; Royal Melbourne Hospital). Multiple lines of computational evidence predict a deleterious effect for this missense substitution (PP3; 5/5 algorithms). Two other variants at an adjacent nucleotide within the same codon have been reported in patients with recessive and dominant DEB and are similarly rare, but both demonstrate a greater differences in physicochemical properties between the wildtype and mutant amino acids. Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM1, PM2, PS4_Supporting, PP3. |