rs121912846

chr3-48575409-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_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: Genomes: not found (cov: 33)
• Consequence: COL7A1 NM_000094.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.65

Genes affected

COL7A1 (HGNC:2214): (collagen type VII alpha 1 chain) This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous epithelia. It functions as an anchoring fibril between the external epithelia and the underlying stroma. Mutations in this gene are associated with all forms of dystrophic epidermolysis bullosa. In the absence of mutations, however, an acquired form of this disease can result from an autoimmune response made to type VII collagen. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000094.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-48575410-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 379455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, COL7A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-48575409-C-T is Pathogenic according to our data. Variant chr3-48575409-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48575409-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL7A1	NM_000094.4	c.6110G>A	p.Gly2037Glu	missense_variant	74/119	ENST00000681320.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL7A1	ENST00000681320.1	c.6110G>A	p.Gly2037Glu	missense_variant	74/119		NM_000094.4	P1
COL7A1	ENST00000328333.12	c.6110G>A	p.Gly2037Glu	missense_variant	73/118	1		P1
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

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Generalized dominant dystrophic epidermolysis bullosa Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2006	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires	Mar 14, 2022	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	29
Dann	Benign	0.96
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.94		Loss of glycosylation at K2038 (P = 0.0175);
MVP		0.98
MPC		0.32
ClinPred		1.0	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.97
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912846; hg19: chr3-48612842;