ClinVar Miner

Submissions for variant NM_000094.3(COL7A1):c.6091G>A (p.Gly2031Ser) (rs121912838)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000335209 SCV000329319 pathogenic not provided 2017-12-12 criteria provided, single submitter clinical testing The G2031S missense variant in the COL7A1 gene was initially published in the homozygous state in monozygotic triplets with dystrophic epidermolysis bullosa (DEB) born to unaffected consanguineous parents who were both heterozygous for the variant (Nordal et al., 2001). The G2031S variant has subsequently been identified in other patients studied at GeneDx and in the literature and has been reported to have either an autosomal recessive or autosomal dominant inheritance pattern depending on the individual, sometimes presenting with the two different inheritance patterns in members of the same family (Almaani et al., 2011; Hamidi et al., 2016; E Pfendner unpublished). The G2031S variantis observed in 6/9548 alleles (0.063%) from individuals of Ashkenazi Jewish background, and6/234,304 global alleles (0.0025%) in large population cohorts (Lek et al., 2016). The G2031S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as it occurs at a Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the COLVII protein. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Multiple other missense variants in the surrounding Glycine residues(G2028W, G2028A, G2028E, G2028R, G2034R, G2034W, G2034V, G2034E) have been reported in the Human Gene Mutation Database in association with DEB, supporting the functional importance of this Gly-X-Y triple helical region of the protein (Stenson et al., 2014). We interpret G2031S as a pathogenic variant.
Invitae RCV000335209 SCV000942901 pathogenic not provided 2020-09-14 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 2031 of the COL7A1 protein (p.Gly2031Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs121912838, ExAC 0.002%). This variant has been observed to be homozygous in several individuals affected with epidermolysis bullosa (PMID: 11167698, 27746867). ClinVar contains an entry for this variant (Variation ID: 17446). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C5). 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 missense 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. 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. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000850543 SCV000992754 uncertain significance Recessive dystrophic epidermolysis bullosa; Pretibial epidermolysis bullosa; Dominant dystrophic epidermolysis bullosa with absence of skin; Transient bullous dermolysis of the newborn; Epidermolysis bullosa pruriginosa; Nail disorder, nonsyndromic congenital, 8; Generalized dominant dystrophic epidermolysis bullosa 2012-09-20 criteria provided, single submitter clinical testing
OMIM RCV000018997 SCV000039284 pathogenic Recessive dystrophic epidermolysis bullosa 2001-01-01 no assertion criteria provided literature only

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