PM1, PM2, PM5, PP2, PP3, PP5
ClinVar Genomic variation as it relates to human health
NM_000094.4(COL7A1):c.6022C>T (p.Arg2008Cys)
Germline
Classification
Help
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.
(10)
Help
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.
Pathogenic/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000094.4(COL7A1):c.6022C>T (p.Arg2008Cys)
Variation ID: 522791 Accession: VCV000522791.35
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 48575497 (GRCh38) [ NCBI UCSC ] 3: 48612930 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Apr 29, 2018 Feb 14, 2024 Sep 11, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000094.4:c.6022C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000085.1:p.Arg2008Cys missense NC_000003.12:g.48575497G>A NC_000003.11:g.48612930G>A NG_007065.1:g.24756C>T LRG_286:g.24756C>T LRG_286t1:c.6022C>T LRG_286p1:p.Arg2008Cys - Protein change
- R2008C
- Other names
- -
- Canonical SPDI
- NC_000003.12:48575496:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00001
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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. |
|||
| COL7A1 | - | - |
GRCh38 GRCh37 |
5220 | 5252 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 3, 2017 | RCV000625955.8 | |
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jun 6, 2022 | RCV000789046.7 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Sep 11, 2023 | RCV001216539.8 |
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
Help
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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|---|---|---|---|---|---|
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Pathogenic
(Dec 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Epidermolysis bullosa dystrophica
Affected status: yes
Allele origin:
inherited
|
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Accession: SCV000746553.1
First in ClinVar: Apr 29, 2018 Last updated: Apr 29, 2018 |
Age: 20-29 years
Sex: female
Geographic origin: Iran
|
|
|
Pathogenic
(Nov 09, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Recessive dystrophic epidermolysis bullosa
Affected status: yes
Allele origin:
germline
|
Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV000928395.1
First in ClinVar: Jul 27, 2019 Last updated: Jul 27, 2019 |
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
|
|
|
Pathogenic
(Jul 09, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001388342.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral … (more)
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2008 of the COL7A1 protein (p.Arg2008Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 9740253, 10084325, 15888141, 16271705, 20184583). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 522791). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL7A1 protein function. This variant disrupts the p.Arg2008 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326325, 10084325, 10504458). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. (less)
|
|
|
Pathogenic
(Mar 08, 2011)
|
criteria provided, single submitter
Method: research
|
Dystrophic epidermolysis bullosa
Affected status: yes
Allele origin:
germline
|
Biomedical Innovation Departament, CIEMAT
Accession: SCV001547337.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Mar 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Recessive dystrophic epidermolysis bullosa
Affected status: yes
Allele origin:
germline
|
Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires
Accession: SCV002499318.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
Number of individuals with the variant: 2
Secondary finding: no
|
|
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Likely pathogenic
(Jun 06, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Recessive dystrophic epidermolysis bullosa
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807900.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 strong
Number of individuals with the variant: 1
Clinical Features:
Primary Caesarian section (present) , Fetal growth restriction (present) , Decreased body weight (present) , Mild intrauterine growth retardation (present) , Caesarian section (present) , … (more)
Primary Caesarian section (present) , Fetal growth restriction (present) , Decreased body weight (present) , Mild intrauterine growth retardation (present) , Caesarian section (present) , Neonatal sepsis (present) , Abnormal blistering of the skin (present) , Nail dystrophy (present) , Anemia (present) , Short stature (present) (less)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
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Pathogenic
(Sep 11, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002526463.3
First in ClinVar: Jun 24, 2022 Last updated: Sep 14, 2023 |
Comment:
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; … (more)
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: 10504458, 16271705, 15816848, 10367730, 27498345, 9740253, 34426522, 20184583, 31001817, 15888141, 10084325, 34008892, 35979658, 36578049, 36287101) (less)
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Recessive dystrophic epidermolysis bullosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100630.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.R2008C in COL7A1 (NM_000094.4) has been reported previously in affected indviduals (Escámez MJ et al,2018). It has been submitted to ClinVar as … (more)
The missense variant p.R2008C in COL7A1 (NM_000094.4) has been reported previously in affected indviduals (Escámez MJ et al,2018). It has been submitted to ClinVar as Pathogenic. Other variants affecting this residue have been reported previously. The p.R2008C variant is observed in 1/1,09,206 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R2008C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.6022 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Abnormal blistering of the skin (present) , Abnormal blistering of the skin (present) , Milia (present) , Pretibial dystrophic epidermolysis bullosa (present)
|
|
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Pathogenic
(Apr 28, 2021)
|
no assertion criteria provided
Method: clinical testing
|
Dystrophic epidermolysis bullosa
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002079226.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Recessive dystrophic epidermolysis bullosa
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Narges Medical Genetic and Prenatal Diagnosis Lab
Accession: SCV004035049.1
First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023 |
|
Comment:
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2008 of the COL7A1 protein (p.Arg2008Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 9740253, 10084325, 15888141, 16271705, 20184583). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 522791). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL7A1 protein function. This variant disrupts the p.Arg2008 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326325, 10084325, 10504458). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Comment:
ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 strong
Comment:
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: 10504458, 16271705, 15816848, 10367730, 27498345, 9740253, 34426522, 20184583, 31001817, 15888141, 10084325, 34008892, 35979658, 36578049, 36287101)
Comment:
The missense variant p.R2008C in COL7A1 (NM_000094.4) has been reported previously in affected indviduals (Escámez MJ et al,2018). It has been submitted to ClinVar as Pathogenic. Other variants affecting this residue have been reported previously. The p.R2008C variant is observed in 1/1,09,206 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R2008C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.6022 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
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. |
Comment:
PM1, PM2, PM5, PP2, PP3, PP5
Comment:
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2008 of the COL7A1 protein (p.Arg2008Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dystrophic epidermolysis bullosa (PMID: 9740253, 10084325, 15888141, 16271705, 20184583). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 522791). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL7A1 protein function. This variant disrupts the p.Arg2008 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326325, 10084325, 10504458). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Comment:
ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 strong
Comment:
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: 10504458, 16271705, 15816848, 10367730, 27498345, 9740253, 34426522, 20184583, 31001817, 15888141, 10084325, 34008892, 35979658, 36578049, 36287101)
Comment:
The missense variant p.R2008C in COL7A1 (NM_000094.4) has been reported previously in affected indviduals (Escámez MJ et al,2018). It has been submitted to ClinVar as Pathogenic. Other variants affecting this residue have been reported previously. The p.R2008C variant is observed in 1/1,09,206 (0.0009%) alleles from individuals of European (Non-Finnish) background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.R2008C missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.6022 in COL7A1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Analysis of COL7A1 pathogenic variants in a large cohort of dystrophic epidermolysis bullosa patients from Argentina reveals a new genotype-phenotype correlation. | Natale MI | American journal of medical genetics. Part A | 2022 | PMID: 35979658 |
| The first COL7A1 mutation survey in a large Spanish dystrophic epidermolysis bullosa cohort: c.6527insC disclosed as an unusually recurrent mutation. | Escámez MJ | The British journal of dermatology | 2010 | PMID: 20184583 |
| Denaturing HPLC-based approach for detection of COL7A1 gene mutations causing dystrophic epidermolysis bullosa. | Posteraro P | Biochemical and biophysical research communications | 2005 | PMID: 16271705 |
| High frequency of the 425A-->G splice-site mutation and novel mutations of the COL7A1 gene in central Europe: significance for future mutation detection strategies in dystrophic epidermolysis bullosa. | Csikós M | The British journal of dermatology | 2005 | PMID: 15888141 |
| Comparative mutation detection screening of the type VII collagen gene (COL7A1) using the protein truncation test, fluorescent chemical cleavage of mismatch, and conformation sensitive gel electrophoresis. | Whittock NV | The Journal of investigative dermatology | 1999 | PMID: 10504458 |
| Clustering of COL7A1 mutations in exon 73: implications for mutation analysis in dystrophic epidermolysis bullosa. | Mecklenbeck S | The Journal of investigative dermatology | 1999 | PMID: 10084325 |
| Novel COL7A1 mutations in dystrophic forms of epidermolysis bullosa. | Kon A | The Journal of investigative dermatology | 1998 | PMID: 9740253 |
| 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 rs1055680335 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Sep 29, 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.