ClinVar Genomic variation as it relates to human health
NM_000094.4(COL7A1):c.6100G>A (p.Gly2034Arg)
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.6100G>A (p.Gly2034Arg)
Variation ID: 17450 Accession: VCV000017450.18
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p21.31 3: 48575419 (GRCh38) [ NCBI UCSC ] 3: 48612852 (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 Oct 8, 2024 Nov 11, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000094.4:c.6100G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000085.1:p.Gly2034Arg missense NC_000003.12:g.48575419C>T NC_000003.11:g.48612852C>T NG_007065.1:g.24834G>A LRG_286:g.24834G>A LRG_286t1:c.6100G>A LRG_286p1:p.Gly2034Arg Q02388:p.Gly2034Arg - Protein change
- G2034R
- Other names
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- Canonical SPDI
- NC_000003.12:48575418: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
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 |
5193 | 5225 |
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. |
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Pathogenic (2) |
no assertion criteria provided
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Mar 1, 2002 | RCV000019001.31 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Nov 11, 2023 | RCV000413086.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 2, 2019 | RCV001352761.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 17, 2022 | RCV002243653.2 | |
COL7A1-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Aug 19, 2024 | RCV003894815.2 |
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
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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Pathogenic
(Dec 02, 2019)
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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: SCV001547343.1
First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021 |
Number of individuals with the variant: 3
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Pathogenic
(Feb 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Generalized dominant dystrophic epidermolysis bullosa
Recessive dystrophic epidermolysis bullosa
Affected status: yes
Allele origin:
germline
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Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV002512607.1
First in ClinVar: May 21, 2022 Last updated: May 21, 2022 |
Comment:
ACMG classification criteria: PS4 strong, PM1 moderate, PM2 moderate, PP1 strong, PP3 supporting
Geographic origin: Brazil
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Pathogenic
(Nov 11, 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: SCV003525539.2
First in ClinVar: Feb 07, 2023 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 2034 of the COL7A1 protein (p.Gly2034Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 2034 of the COL7A1 protein (p.Gly2034Arg). This variant is present in population databases (rs121912844, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal dominant epidermolysis bullosa dystrophica (PMID: 9347800). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17450). 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
(May 16, 2023)
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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: SCV000490497.2
First in ClinVar: Jan 09, 2017 Last updated: May 27, 2023 |
Comment:
One of the most common pathogenic variants in individuals with autosomal dominant dystrophic epidermolysis bullosa (DDEB); G2034R and G2043R account for up 50% of the … (more)
One of the most common pathogenic variants in individuals with autosomal dominant dystrophic epidermolysis bullosa (DDEB); G2034R and G2043R account for up 50% of the DDEB pathogenic variants reported in the largest US cohort (Varki et al., 2007; Pfendner and Lucky, 2018); 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); 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: 25113066, 21448560, 11874498, 10084325, 9856844, 2653224, 9215684, 31001817, 34046686, 32484238, 11218887, 33274474, 9347800, 16971478, 34543471) (less)
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Pathogenic
(Mar 01, 2002)
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no assertion criteria provided
Method: literature only
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EPIDERMOLYSIS BULLOSA DYSTROPHICA, AUTOSOMAL DOMINANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039288.4
First in ClinVar: Apr 04, 2013 Last updated: Jun 09, 2022 |
Comment on evidence:
In affected members of a large family with autosomal dominant epidermolysis bullosa dystrophica of the Cockayne-Touraine type (131750), Kon et al. (1997) identified a heterozygous … (more)
In affected members of a large family with autosomal dominant epidermolysis bullosa dystrophica of the Cockayne-Touraine type (131750), Kon et al. (1997) identified a heterozygous 6100G-A transition in exon 73 of the COL7A1 gene, resulting in a gly2034-to-arg (G2034R) substitution. Hammami-Hauasli et al. (1998) and Mecklenbeck et al. (1999) also found the G2034R mutation in 2 additional families with DDEB, although specific phenotypic subtypes were not reported. Martinez-Mir et al. (2002) identified heterozygosity for the G2034R substitution in affected members of a family with an unusual epidermolysis bullosa phenotype. The family was first reported by Fine et al. (1989) as epidermolysis bullosa simplex superficialis (607600) because skin biopsies showed clefts of variable size just below the stratum corneum or intraepidermal without changes in the sublamina densa. However, the clinical features also included those reminiscent of dominant dystrophic EB, including scarring, milia, nail dystrophy, and blistering involving the oral cavity. Based on the molecular findings, Martinez-Mir et al. (2002) reclassified the phenotype in this family as a clinical variant of dominant dystrophic epidermolysis bullosa. (less)
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Pathogenic
(Aug 19, 2024)
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no assertion criteria provided
Method: clinical testing
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COL7A1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004712866.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The COL7A1 c.6100G>A variant is predicted to result in the amino acid substitution p.Gly2034Arg. This variant has been reported in many individuals with dystrophic epidermolysis … (more)
The COL7A1 c.6100G>A variant is predicted to result in the amino acid substitution p.Gly2034Arg. This variant has been reported in many individuals with dystrophic epidermolysis bullosa (see for example, Kon et al. 1997. PubMed ID: 9347800; Mariath et al. 2019. PubMed ID: 31001817; Chen et al. 2020. PubMed ID: 32484238). This variant resides in exon 73 and results in a glycine amino acid substitution. Glycine substitution variants in the triple helical domain (Gly-X-Y; especially in exons 73, 74, and 75) are predominant in autosomal dominant dystrophic epidermolysis bullosa (DDEB; https://www.ncbi.nlm.nih.gov/books/NBK1304/). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. (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: SCV001741206.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
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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: SCV001959611.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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not provided
(-)
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no classification provided
Method: literature only
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Generalized dominant dystrophic epidermolysis bullosa
Affected status: unknown
Allele origin:
germline
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GeneReviews
Accession: SCV004023209.1
First in ClinVar: Aug 05, 2023 Last updated: Aug 05, 2023 |
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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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Dystrophic Epidermolysis Bullosa. | Adam MP | - | 2018 | PMID: 20301481 |
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 |
EB simplex superficialis resulting from a mutation in the type VII collagen gene. | Martinez-Mir A | The Journal of investigative dermatology | 2002 | PMID: 11874498 |
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 |
Transient bullous dermolysis of the newborn associated with compound heterozygosity for recessive and dominant COL7A1 mutations. | Hammami-Hauasli N | The Journal of investigative dermatology | 1998 | PMID: 9856844 |
Novel glycine substitution mutations in COL7A1 reveal that the Pasini and Cockayne-Touraine variants of dominant dystrophic epidermolysis bullosa are allelic. | Kon A | The Journal of investigative dermatology | 1997 | PMID: 9347800 |
Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution. | Bella J | Science (New York, N.Y.) | 1994 | PMID: 7695699 |
Intracytoplasmic retention of type VII collagen and dominant dystrophic epidermolysis bullosa: reversal of defect following cessation of or marked improvement in disease activity. | Fine JD | The Journal of investigative dermatology | 1993 | PMID: 8345225 |
Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence. | Long CG | Biochemistry | 1993 | PMID: 8218237 |
Text-mined citations for rs121912844 ...
HelpRecord last updated Oct 13, 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.