rs121912842
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000094.4(COL7A1):c.6017G>A(p.Gly2006Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2006A) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
COL7A1
NM_000094.4 missense
NM_000094.4 missense
Scores
17
2
Clinical Significance
Conservation
PhyloP100: 6.14
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 19 ACMG points.
PM1
?
In a hotspot region, there are 7 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 chr3-48575502-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2203368.Status of the report is criteria_provided_single_submitter, 1 stars.
PP2
?
Missense variant where missense usually causes diseases, COL7A1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
?
Variant 3-48575502-C-T is Pathogenic according to our data. Variant chr3-48575502-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.6017G>A | p.Gly2006Asp | missense_variant | 74/119 | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.6017G>A | p.Gly2006Asp | missense_variant | 74/119 | NM_000094.4 | P1 | ||
COL7A1 | ENST00000328333.12 | c.6017G>A | p.Gly2006Asp | missense_variant | 73/118 | 1 | P1 | ||
COL7A1 | ENST00000487017.5 | n.1934G>A | non_coding_transcript_exon_variant | 39/83 | 5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 39
GnomAD4 exome
Cov.:
39
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Generalized dominant dystrophic epidermolysis bullosa Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota | Jan 13, 2021 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 24, 1998 | - - |
COL7A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 23, 2024 | The COL7A1 c.6017G>A variant is predicted to result in the amino acid substitution p.Gly2006Asp. This variant was documented in a family with autosomal dominant epidermolysis bullosa (Hammami-Hauasli et al. 1998. PubMed ID: 9668111). This variant resides in exon 73 and results in a glycine residue substitution. Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) are predominant in autosomal dominant dystrophic epidermolysis bullosa (DDEB; https://www.ncbi.nlm.nih.gov/books/NBK1304/). Functional studies support its pathogenicity (Fritsch et al. 2009. PubMed ID: 19726672). In addition, other missense changes at the same amino-acid position (p.Gly2006Ala and p.Gly2006Ser) have also been documented in individuals with autosomal dominant epidermolysis bullosa (Whittock et al. 1999. PubMed ID: 10504458; Mallipeddi et al. 2003. PubMed ID: 14616374). The c.6017G>A (p.Gly2006Asp) variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In summary, this variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of glycosylation at K2005 (P = 0.0028);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at