Submissions for variant NM_000094.4(COL7A1):c.8245G>A (p.Gly2749Arg)

gnomAD frequency: 0.00001  dbSNP: rs121912853

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378411	SCV001575972	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2749 of the COL7A1 protein (p.Gly2749Arg). This variant is present in population databases (rs121912853, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive dystrophic epidermolysis bullosa (PMID: 8644729, 29334134, 29473190). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17460). 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%. Experimental studies have shown that this missense change affects COL7A1 function (PMID: 18450758). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000019011	SCV003921900	pathogenic	Recessive dystrophic epidermolysis bullosa	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with dystrophic epidermolysis bullosa (DEB) (OMIM, PMID: 31670143). (I) 0108 - This gene is associated with both recessive and dominant disease. The spectrum of DEB associated with this gene can be either dominant or recessive. Dominant inheritance (DDEB; MIM#131750) is typically associated with milder phenotypes, whereas recessive inheritance (RDEB; MIM#226600) is usually observed in more severe cases (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Severity ranges from involving exclusively nails, to generalized and severe blistering and scarring (PMID: 31670143). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 4 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional G-X-Y motif within a collagen domain (DECIPHER). (SP) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A change to valine was regarded as likely pathogenic in LOVD. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been submitted as likely pathogenic and pathogenic in ClinVar. In addition, it has been reported in multiple individuals with autosomal recessive dystrophic epidermolysis bullosa (PMIDs: 8644729, 29473190, 29334134, 22209565). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfection studies demonstrated that mutant impaired protein stability and resulted in inability to form trimers (PMID: 11698408). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
GeneDx	RCV001378411	SCV005079043	pathogenic	not provided	2023-12-13	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); 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: 25525159, 21448560, 29334134, 8644729, 29473190, 34435747)
OMIM	RCV000019011	SCV000039298	pathogenic	Recessive dystrophic epidermolysis bullosa	1996-04-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001826480	SCV002079185	likely pathogenic	Epidermolysis bullosa dystrophica	2021-08-02	no assertion criteria provided	clinical testing