Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001389450 | SCV001590825 | pathogenic | not provided | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2680 of the COL7A1 protein (p.Gly2680Ser). This variant is present in population databases (rs370744140, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive epidermolysis bullosa dystrophica (PMID: 22266148, 29531004, 31634165). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1075764). 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%. 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. |
| 3billion | RCV002051943 | SCV002318548 | pathogenic | Recessive dystrophic epidermolysis bullosa | 2022-03-22 | criteria provided, single submitter | clinical testing | The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 31634165, 29531004, 22266148, PM3_S) and reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated families (PMID: 31634165). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:21448560). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.888>=0.6, 3CNET: 0.931>=0.75). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000199). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. |
| Rare Diseases Genetics and Genomics, |
RCV002051943 | SCV002818463 | pathogenic | Recessive dystrophic epidermolysis bullosa | 2022-09-12 | no assertion criteria provided | clinical testing |