ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.6262G>A (p.Gly2088Arg) (rs573432153)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414533 SCV000490502 pathogenic not provided 2021-04-19 criteria provided, single submitter clinical testing Located in the highly conserved Gly-X-Y repeat of the collagenous domain; Glycine substitution variants in this region of the COLVII protein destabilize the collagen triple helix resulting in skin fragility due to poor anchoring of the basement membrane to the underlying dermis (Pfendner and Lucky, 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21448560, 25525159, 20555349)
Invitae RCV000414533 SCV001416054 likely pathogenic not provided 2020-08-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 2088 of the COL7A1 protein (p.Gly2088Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs573432153, ExAC 0.006%). This variant has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 20555349). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 372344). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Gly2088 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been observed in individuals with COL7A1-related conditions (PMID: 16965439), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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