ClinVar Genomic variation as it relates to human health

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28168442, 24317394, 20301481, 29500833, 29625052, 26689913, 34426522, 23786535, 16971478, 10504458)

This sequence change creates a premature translational stop signal (p.Gly1281Valfs*44) in the COL7A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL7A1 are known to be pathogenic (PMID: 16971478). This variant is present in population databases (rs757688782, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with epidermolysis bullosa dystrophica (PMID: 10504458, 16971478, 23786535, 24317394). 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: 372332). For these reasons, this variant has been classified as Pathogenic.

0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dystrophic epidermolysis bullosa (OMIM, PMID: 31670143). (I) 0108 - This gene is associated with both recessive and dominant disease. The spectrum of dystrophic epidermolysis bullosa associated with this gene can be either autosomal dominant or recessive inheritance. Autosomal dominant epidermolysis bullosa dystrophica (MIM#131750) is typically associated with milder phenotypes, whereas autosomal recessive epidermolysis bullosa dystrophica (MIM#226600) is usually observed in more severe cases (OMIM). Premature termination variants resulting in complete absence of protein are usually associated with the most severe recessive dystrophic epidermolysis bullosa (PMID: 32506467). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (5 heterozygotes, 0 homozygotes). (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two individuals with recessive epidermolysis bullosa (PMIDs: 26446410, 23786535), and as pathogenic by multiple clinical testing laboratories (ClinVar). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

COL7A1: PM3:Very Strong, PVS1, PM2, PP4