This missense variant replaces glycine with aspartic acid at codon 333 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in three individuals affected with vascular Ehlers-Danlos syndrome (PMID: 24922459, LOVD DB individual #00431606). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000090.4(COL3A1):c.998G>A (p.Gly333Asp)
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.
(4)
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.
Likely pathogenic
4
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000090.4(COL3A1):c.998G>A (p.Gly333Asp)
Variation ID: 101430 Accession: VCV000101430.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q32.2 2: 188992888 (GRCh38) [ NCBI UCSC ] 2: 189857614 (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 Mar 13, 2014 Apr 20, 2024 Jun 26, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000090.4:c.998G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000081.2:p.Gly333Asp missense NC_000002.12:g.188992888G>A NC_000002.11:g.189857614G>A NG_007404.1:g.23516G>A LRG_3:g.23516G>A LRG_3t1:c.998G>A LRG_3p1:p.Gly333Asp NP_000081.1:p.Gly333Asp - Protein change
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- Other names
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- Canonical SPDI
- NC_000002.12:188992887: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.
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- 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 | ||
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| 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. |
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| COL3A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3041 | 3169 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 26, 2023 | RCV000087668.8 |
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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Likely Pathogenic
(Jun 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, type 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004832536.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
This missense variant replaces glycine with aspartic acid at codon 333 of the COL3A1 protein. This variant changes one of the conserved glycine residues within … (more)
This missense variant replaces glycine with aspartic acid at codon 333 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in three individuals affected with vascular Ehlers-Danlos syndrome (PMID: 24922459, LOVD DB individual #00431606). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(May 02, 2016)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, type 4
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000695381.1
First in ClinVar: Mar 13, 2014 Last updated: Mar 13, 2014 |
Comment:
Variant summary: The c.998G>A variant affects a conserved nucleotide, resulting in amino acid change from critical codon Gly to Asp in the triple helical region … (more)
Variant summary: The c.998G>A variant affects a conserved nucleotide, resulting in amino acid change from critical codon Gly to Asp in the triple helical region of the COL3A1 protein. 5/5 in-silico tools predict damaging outcome for this variant. This variant is not found in 121038 control chromosomes. This variant has been reported in two EDS-type IV patients and was classified as a causative mutation (Pepin_Genet Med_2014). In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as likely pathogenic until more information becomes available. (less)
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Likely pathogenic
(May 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, type 4
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004293007.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the triple helix domain of COL3A1. 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). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 101430). This missense change has been observed in individual(s) with arterial dissection and/or Ehlers-Danlos syndrome (PMID: 24922459; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 333 of the COL3A1 protein (p.Gly333Asp). (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Ehlers-Danlos syndrome, type 4
Affected status: yes
Allele origin:
germline
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Collagen Diagnostic Laboratory, University of Washington
Accession: SCV000120560.1
First in ClinVar: Mar 13, 2014 Last updated: Mar 13, 2014 |
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Comment:
Comment:
Variant summary: The c.998G>A variant affects a conserved nucleotide, resulting in amino acid change from critical codon Gly to Asp in the triple helical region of the COL3A1 protein. 5/5 in-silico tools predict damaging outcome for this variant. This variant is not found in 121038 control chromosomes. This variant has been reported in two EDS-type IV patients and was classified as a causative mutation (Pepin_Genet Med_2014). In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as likely pathogenic until more information becomes available.
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the triple helix domain of COL3A1. 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). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 101430). This missense change has been observed in individual(s) with arterial dissection and/or Ehlers-Danlos syndrome (PMID: 24922459; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 333 of the COL3A1 protein (p.Gly333Asp).
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:
This missense variant replaces glycine with aspartic acid at codon 333 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been reported in three individuals affected with vascular Ehlers-Danlos syndrome (PMID: 24922459, LOVD DB individual #00431606). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Comment:
Variant summary: The c.998G>A variant affects a conserved nucleotide, resulting in amino acid change from critical codon Gly to Asp in the triple helical region of the COL3A1 protein. 5/5 in-silico tools predict damaging outcome for this variant. This variant is not found in 121038 control chromosomes. This variant has been reported in two EDS-type IV patients and was classified as a causative mutation (Pepin_Genet Med_2014). In addition, one clinical laboratory classified this variant as pathogenic. Taken together, this variant was classified as likely pathogenic until more information becomes available.
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the triple helix domain of COL3A1. 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). In COL3A1, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 101430). This missense change has been observed in individual(s) with arterial dissection and/or Ehlers-Danlos syndrome (PMID: 24922459; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 333 of the COL3A1 protein (p.Gly333Asp).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers-Danlos syndrome. | Frank M | European journal of human genetics : EJHG | 2015 | PMID: 25758994 |
| Survival is affected by mutation type and molecular mechanism in vascular Ehlers-Danlos syndrome (EDS type IV). | Pepin MG | Genetics in medicine : official journal of the American College of Medical Genetics | 2014 | PMID: 24922459 |
| Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
| 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 rs587779673 ...
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.