chr3-48576249-C-T
Variant names:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong
The NM_000094.4(COL7A1):c.5820G>A(p.Pro1940Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
COL7A1
NM_000094.4 synonymous
NM_000094.4 synonymous
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
Conservation
PhyloP100: -0.234
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PP5
Variant 3-48576249-C-T is Pathogenic according to our data. Variant chr3-48576249-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-48576249-C-T is described in Lovd as [Pathogenic]. Variant chr3-48576249-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.5820G>A | p.Pro1940Pro | synonymous_variant | Exon 71 of 119 | NM_000094.4 | ENSP00000506558.1 | |||
COL7A1 | ENST00000328333.12 | c.5820G>A | p.Pro1940Pro | synonymous_variant | Exon 70 of 118 | 1 | ENSP00000332371.8 | |||
COL7A1 | ENST00000487017.5 | n.1737G>A | splice_region_variant, non_coding_transcript_exon_variant | Exon 36 of 83 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000877 AC: 22AN: 250822Hom.: 0 AF XY: 0.000111 AC XY: 15AN XY: 135716
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GnomAD4 exome AF: 0.000114 AC: 166AN: 1461382Hom.: 0 Cov.: 34 AF XY: 0.000103 AC XY: 75AN XY: 726970
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GnomAD4 genome AF: 0.0000986 AC: 15AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7AN XY: 74352
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2025 | This sequence change affects codon 1940 of the COL7A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL7A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs200972872, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9804332, 31001817, 31930626). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 431810). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 70, but is expected to preserve the integrity of the reading-frame (PMID: 9804332). 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. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2023 | RNA studies demonstrate that the variant reduces the quality of the splice donor site in intron 70, causing abnormal gene splicing and exon skipping of exon 70, in approximately 40% of transcripts (PMID: 9804332); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33969388, 9804332, 21448560, 12485454, 31589614, 34426522, 31001817, 31930626, 33274474) - |
COL7A1-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2023 | Variant summary: COL7A1 c.5820G>A (p.Pro1940Pro) results in a synonymous change to the encoded protein sequence and also alters the last nucleotide of Exon 71 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: two predict the variant abolishes a 5' splicing donor site, and two predict the variant weakens the same 5' donor site. At least two publications report experimental evidence that this variant affects mRNA splicing, leading to both exon skipping and intron retention (e.g., Terracina_1998, Vahidnezhad_2020). The variant allele was found at a frequency of 8.8e-05 in 250822 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5820G>A has been reported in the literature in both homozygous and compound heterozygous individuals affected with Dystrophic Epidermolysis Bullosa, Recessive (e.g., Terracina_1998, Gardella_2002, Vahidnezhad_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating the impact of the variant, finding markedly reduced COL7A1 transcript levels in a whole-skin biopsy from a homozgyous patient (e.g., Vahidnezhad_2020). The following publications have been ascertained in the context of this evaluation (PMID: 12485454, 9804332, 31930626). Seven submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations (pathogenic, n = 5; likely pathogenic, n = 1; VUS, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 24, 2024 | The COL7A1 c.5820G>A variant is not predicted to result in an amino acid change (p.=). This variant leads to skipping of exon 70 of the COL7A1 gene (Terracina et al. 1998. PubMed ID: 9804332). This variant has been reported in the compound heterozygous state in an individual with a mild form of dystrophic epidermolysis bullosa (Terracina et al. 1998. PubMed ID: 9804332; Supplementary Table SII, Almaani et al. 2011. PubMed ID: 21448560; Mariath et al. 2019. PubMed ID: 31001817). This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Recessive dystrophic epidermolysis bullosa;C0268371:Dominant dystrophic epidermolysis bullosa with absence of skin;C0432321:Pretibial dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa;C1275114:Epidermolysis bullosa pruriginosa;C1843761:Nonsyndromic congenital nail disorder 8;C1851573:Transient bullous dermolysis of the newborn Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Epidermolysis bullosa dystrophica Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Nov 26, 2018 | - - |
Recessive dystrophic epidermolysis bullosa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires | Mar 14, 2022 | - - |
Epidermolysis bullosa dystrophica inversa, autosomal recessive Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Epidermolysis bullosa dystrophica, autosomal recessive, localisata variant Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 1998 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at