ClinVar Genomic variation as it relates to human health
NM_000094.4(COL7A1):c.6187C>T (p.Arg2063Trp)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000094.4(COL7A1):c.6187C>T (p.Arg2063Trp)
Variation ID: 17456 Accession: VCV000017456.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 48575236 (GRCh38) [ NCBI UCSC ] 3: 48612669 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 10, 2016 Feb 14, 2024 Jan 28, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000094.4:c.6187C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000085.1:p.Arg2063Trp missense NM_000094.3:c.[6187C>T] NC_000003.12:g.48575236G>A NC_000003.11:g.48612669G>A NG_007065.1:g.25017C>T LRG_286:g.25017C>T LRG_286t1:c.6187C>T LRG_286p1:p.Arg2063Trp Q02388:p.Arg2063Trp - Protein change
- R2063W
- Other names
- -
- Canonical SPDI
- NC_000003.12:48575235:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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COL7A1 | - | - |
GRCh38 GRCh37 |
5127 | 5158 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, single submitter
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- | RCV000019007.27 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 28, 2023 | RCV000413807.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2017 | RCV001352769.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Oct 31, 2017)
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criteria provided, single submitter
Method: research
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Dystrophic epidermolysis bullosa
Affected status: yes
Allele origin:
germline
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Biomedical Innovation Departament, CIEMAT
Accession: SCV001547351.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Number of individuals with the variant: 2
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Pathogenic
(Nov 02, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490501.5
First in ClinVar: Jan 09, 2017 Last updated: Mar 04, 2023 |
Comment:
Reported previously in the homozygous state or with a second COL7A1 variant in patients with autosomal recessive DEB (Hovnanian et al., 1997; Hashimoto et al., … (more)
Reported previously in the homozygous state or with a second COL7A1 variant in patients with autosomal recessive DEB (Hovnanian et al., 1997; Hashimoto et al., 1999; Gardella et al., 2002; Kern et al., 2009; Ben Brick et al., 2014; Kopeckova et al., 2016; Chen et al., 2020); Identified in unrelated patients with generalized DEB as a single heterozygous variant with no second COL7A1 variant identified (Posteraro et al., 2005; Escamez et al., 2010; Ben Brick et al., 2014; Danescu et al., 2015); Published functional studies demonstrate that this variant is located next to the helical interruption hinge region and results in local triple helix destabilization, and fibroblasts with this variant exhibit decreased motility and adhesion in vitro (Woodley et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); 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: 20184583, 33969388, 21448560, 12207583, 19681861, 10232406, 18558993, 16271705, 12880418, 25201089, 15115517, 18030675, 26707537, 28830826, 34426522, 24170138, 35314946, 32484238, 9326325, 18450758) (less)
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Pathogenic
(Jan 28, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001578934.3
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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. ClinVar contains an entry for this variant (Variation ID: 17456). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 9326325, 12207583, 28830826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs121912849, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 2063 of the COL7A1 protein (p.Arg2063Trp). Experimental studies have shown that this missense change affects COL7A1 function (PMID: 18450758). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Recessive dystrophic epidermolysis bullosa
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002073249.1
First in ClinVar: Feb 04, 2022 Last updated: Feb 04, 2022 |
Comment:
The missense variant p.R2063W in COL7A1 (NM_000094.3) has been previously reported in affected patients (Ben Brick et al., 2014).Functional studies have demonstrated a damaging effect. … (more)
The missense variant p.R2063W in COL7A1 (NM_000094.3) has been previously reported in affected patients (Ben Brick et al., 2014).Functional studies have demonstrated a damaging effect. The variant has been submitted to ClinVar as Pathogenic. The p.R2063W variant is observed in 2/1,13,580 (0.0018%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Localized skin lesion (present) , Syndactyly (present) , Pretibial dystrophic epidermolysis bullosa (present)
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Pathogenic
(Feb 01, 2008)
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no assertion criteria provided
Method: literature only
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EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL RECESSIVE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039294.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 10, 2016 |
Comment on evidence:
In 3 brothers, born of consanguineous parents, with epidermolysis bullosa dystrophica (226600), Hovnanian et al. (1997) identified a homozygous 6187C-T transition in exon 74 of … (more)
In 3 brothers, born of consanguineous parents, with epidermolysis bullosa dystrophica (226600), Hovnanian et al. (1997) identified a homozygous 6187C-T transition in exon 74 of the COL7A1 gene, resulting in an arg2063-to-trp (R2063W) substitution. The boys showed marked phenotypic variability, with the eldest being most severely affected, the middle brother having intermediate severity, and the youngest having a milder, localized form of the disorder. In the family reported by Hovnanian et al. (1997), Titeux et al. (2008) found that disease severity was not correlated with residual COL7A1 mRNA or protein levels, but was correlated with residual protein at the dermal-epidermal junction, suggesting increased degradation. The 2 most severely affected boys had increased mRNA and protein levels of interstitial collagenase (MMP1; 120353), and they were found to carry a SNP in the MMP1 gene (120353.0001) that resulted in increased transcription of MMP1, greater COL7A1 degradation, and thus more severe disease manifestations. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Multigene Next-Generation Sequencing Panel Identifies Pathogenic Variants in Patients with Unknown Subtype of Epidermolysis Bullosa: Subclassification with Prognostic Implications. | Vahidnezhad H | The Journal of investigative dermatology | 2017 | PMID: 28830826 |
Characterization of molecular mechanisms underlying mutations in dystrophic epidermolysis bullosa using site-directed mutagenesis. | Woodley DT | The Journal of biological chemistry | 2008 | PMID: 18450758 |
A frequent functional SNP in the MMP1 promoter is associated with higher disease severity in recessive dystrophic epidermolysis bullosa. | Titeux M | Human mutation | 2008 | PMID: 18030675 |
Different phenotypes in recessive dystrophic epidermolysis bullosa patients sharing the same mutation in compound heterozygosity with two novel mutations in the type VII collagen gene. | Gardella R | The British journal of dermatology | 2002 | PMID: 12207583 |
Characterization of 18 new mutations in COL7A1 in recessive dystrophic epidermolysis bullosa provides evidence for distinct molecular mechanisms underlying defective anchoring fibril formation. | Hovnanian A | American journal of human genetics | 1997 | PMID: 9326325 |
Text-mined citations for rs121912849 ...
HelpRecord last updated Apr 06, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.