rs121912846
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000094.4(COL7A1):c.6110G>A(p.Gly2037Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2037R) has been classified as Pathogenic.
Frequency
Consequence
NM_000094.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.6110G>A | p.Gly2037Glu | missense_variant | 74/119 | ENST00000681320.1 | NP_000085.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.6110G>A | p.Gly2037Glu | missense_variant | 74/119 | NM_000094.4 | ENSP00000506558.1 | |||
COL7A1 | ENST00000328333.12 | c.6110G>A | p.Gly2037Glu | missense_variant | 73/118 | 1 | ENSP00000332371.8 | |||
COL7A1 | ENST00000487017.5 | n.2027G>A | non_coding_transcript_exon_variant | 39/83 | 5 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 39
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Generalized dominant dystrophic epidermolysis bullosa Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires | Mar 14, 2022 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2006 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 02, 2016 | The p.G2037E pathogenic variant in the COL7A1 gene has been reported previously (Jonkman et al., 1999, Sawamura et al., 2005, 2006, Almaani et al 2011). The p.G2037E variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The p.G2037E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function as it occurs at the first Glycine position of the canonical Gly-X-Y repeat in the collagenous domain of the colVII protein. Glycine substitution variants in this region of the collagen VII protein will destabilize the collagen triple helix resulting in anchoring fibrils that are fragile and result in poor anchoring off the basement membrane to the underlying dermis. Missense variants in nearby residues (G2034R, E, W, V, G2040S, V, D) have been reported in the Human Gene Mutation Database in association with DEB (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret p.G2037E as a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at