3-48572712-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong
The NM_000094.4(COL7A1):c.6859G>A(p.Gly2287Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G2287G) has been classified as Likely 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 | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.6859G>A | p.Gly2287Arg | missense_variant | 88/119 | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.6859G>A | p.Gly2287Arg | missense_variant | 88/119 | NM_000094.4 | P1 | ||
COL7A1 | ENST00000328333.12 | c.6859G>A | p.Gly2287Arg | missense_variant | 87/118 | 1 | P1 | ||
COL7A1 | ENST00000487017.5 | n.2776G>A | non_coding_transcript_exon_variant | 53/83 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1456534Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 724130
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 09, 2020 | 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: 21269315, 21448560, 25525159, 29963685, 11260188, 7577595, 10469344, 15113589, 21892539, 16923137, 29334134) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 23, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly2287 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been observed in individuals with COL7A1-related conditions (PMID: 16271705, 31709745), which suggests that this may be a clinically significant amino acid residue. This variant disrupts the triple helix domain of COL7A1. 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 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. This sequence change replaces glycine with arginine at codon 2287 of the COL7A1 protein (p.Gly2287Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with autosomal dominant dystrophic epidermolysis bullosa (PMID: 29963685, 21269315, 10469344). It has also been observed to segregate with disease in related individuals. This variant has been reported in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 10469344); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 17447). 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. 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Epidermolysis bullosa dystrophica Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Dec 22, 2017 | - - |
Recessive dystrophic epidermolysis bullosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1999 | - - |
Nonsyndromic congenital nail disorder 8 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1999 | - - |
COL7A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported as a compound heterozygous change and heterozygous change in patients with epidermolysis bullosa dystrophica (PMID: 10469344). Both autosomal recessive and dominant inheritance have been described for this variant (PMID: 21448560, 21269315, 29963685). It is absent from the gnomAD population database and thus is presumed to be rare. The c.6859G>A (p.Gly2287Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Different amino acid changes at the same codon have also been reported in patients with epidermolysis bullosa dystrophica (PMID: 16271705, 21448560, 31709745). Based on the available evidence, the c.6859G>A (p.Gly2287Arg) variant is classified as Pathogenic. - |
Generalized dominant dystrophic epidermolysis bullosa Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at