ClinVar Genomic variation as it relates to human health
NM_000094.4(COL7A1):c.7957G>A (p.Gly2653Arg)
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.7957G>A (p.Gly2653Arg)
Variation ID: 17458 Accession: VCV000017458.33
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 48567736 (GRCh38) [ NCBI UCSC ] 3: 48605169 (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 Sep 16, 2024 Apr 17, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000094.4:c.7957G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000085.1:p.Gly2653Arg missense NC_000003.12:g.48567736C>T NC_000003.11:g.48605169C>T NG_007065.1:g.32517G>A LRG_286:g.32517G>A LRG_286t1:c.7957G>A LRG_286p1:p.Gly2653Arg Q02388:p.Gly2653Arg - Protein change
- G2653R
- Other names
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- Canonical SPDI
- NC_000003.12:48567735:C:T
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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
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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 |
5190 | 5222 |
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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Mar 14, 2022 | RCV000019009.30 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Apr 17, 2024 | RCV001203194.13 | |
Likely pathogenic (1) |
no assertion criteria provided
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Aug 31, 2020 | RCV001826479.2 |
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
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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
(Mar 14, 2022)
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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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Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires
Accession: SCV002499350.1
First in ClinVar: Aug 29, 2022 Last updated: Aug 29, 2022 |
Number of individuals with the variant: 11
Family history: yes
Secondary finding: no
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Pathogenic
(Apr 17, 2024)
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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: SCV002061005.3
First in ClinVar: Jan 22, 2022 Last updated: Sep 16, 2024 |
Comment:
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 … (more)
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 (PMID: 20301481); Not observed at a 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: 21448560, 15509587, 8644729, 14616374, 9668111, 14516194, 9375848, 31001817, 31589614, 36419915, 34826142, 35979658, 33274474) (less)
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Pathogenic
(Nov 27, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001374346.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2653 of the COL7A1 protein (p.Gly2653Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2653 of the COL7A1 protein (p.Gly2653Arg). This variant is present in population databases (rs121912851, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 8644729, 31001817, 33274474, 34826142). 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: 17458). 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 with a positive predictive value of 95%. 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. (less)
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Pathogenic
(Apr 01, 1996)
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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: SCV000039296.2
First in ClinVar: Apr 04, 2013 Last updated: Oct 10, 2016 |
Comment on evidence:
In a 3-year-old boy with autosomal recessive epidermolysis bullosa dystrophica (226600), Christiano et al. (1996) identified compound heterozygosity for 2 mutations in the COL7A1 gene: … (more)
In a 3-year-old boy with autosomal recessive epidermolysis bullosa dystrophica (226600), Christiano et al. (1996) identified compound heterozygosity for 2 mutations in the COL7A1 gene: a 7597G-A transition in exon 107 resulting in a gly2653-to-arg (G2653R) substitution, and a 7411C-T transition in exon 97 resulting in an arg2471-to-ter (R2471X; 120120.0037) substitution. The patient had a severe phenotype, with generalized blistering since birth and skin missing from the left thumb and both feet, whereas the heterozygous parents and younger brother were unaffected. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001739812.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(Aug 31, 2020)
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no assertion criteria provided
Method: clinical testing
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Dystrophic epidermolysis bullosa
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002079197.1
First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001955427.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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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 |
Otological complications in inversa type recessive dystrophic epidermolysis bullosa. | Robertson SJ | Clinical and experimental dermatology | 2022 | PMID: 34826142 |
Immunofluorescence mapping, electron microscopy and genetics in the diagnosis and sub-classification of inherited epidermolysis bullosa: a single-centre retrospective comparative study of 87 cases with long-term follow-up. | Rossi S | Journal of the European Academy of Dermatology and Venereology : JEADV | 2021 | PMID: 33274474 |
An overview of the genetic basis of epidermolysis bullosa in Brazil: discovery of novel and recurrent disease-causing variants. | Mariath LM | Clinical genetics | 2019 | PMID: 31001817 |
The COL7A1 mutation database. | Wertheim-Tysarowska K | Human mutation | 2012 | PMID: 22058051 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
Glycine substitutions in the triple-helical region of type VII collagen result in a spectrum of dystrophic epidermolysis bullosa phenotypes and patterns of inheritance. | Christiano AM | American journal of human genetics | 1996 | PMID: 8644729 |
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. | Bella J | Science (New York, N.Y.) | 1994 | PMID: 7695699 |
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence. | Long CG | Biochemistry | 1993 | PMID: 8218237 |
Text-mined citations for rs121912851 ...
HelpRecord 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.