ClinVar Genomic variation as it relates to human health
NM_000090.4(COL3A1):c.547G>A (p.Gly183Ser)
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_000090.4(COL3A1):c.547G>A (p.Gly183Ser)
Variation ID: 17228 Accession: VCV000017228.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q32.2 2: 188988099 (GRCh38) [ NCBI UCSC ] 2: 189852825 (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 Feb 20, 2024 Sep 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000090.4:c.547G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000081.2:p.Gly183Ser missense NC_000002.12:g.188988099G>A NC_000002.11:g.189852825G>A NG_007404.1:g.18727G>A LRG_3:g.18727G>A LRG_3t1:c.547G>A LRG_3p1:p.Gly183Ser P02461:p.Gly183Ser NP_000081.1:p.Gly183Ser - Protein change
- Other names
- G16S
- Canonical SPDI
- NC_000002.12:188988098: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
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The frequency of the allele represented by this VCV record.
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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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COL3A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
2994 | 3119 |
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
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Sep 25, 2023 | RCV000018768.40 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 10, 2017 | RCV000479050.1 | |
Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 4, 2019 | RCV001186047.4 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
(Feb 10, 2017)
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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: SCV000568644.3
First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017 |
Comment:
The G183S pathogenic variant was identified in the COL3A1 gene. G183S, described as G16S in some publications due to alternative nomenclature, was initially reported in … (more)
The G183S pathogenic variant was identified in the COL3A1 gene. G183S, described as G16S in some publications due to alternative nomenclature, was initially reported in seven unrelated families with vascular EDS who experienced both arterial and gastrointestinal complications of the condition (Pepin et al., 2000). Furthermore, cultured fibroblasts from the probands of these families were reported to produce abnormal type III procollagen (Pepin et al., 2000). This pathogenic variant was also reported in two other unrelated individuals with a clinical diagnosis of vascular EDS (Mortani et al., 2011; Frank et al., 2015). In addition, G183S is classified as pathogenic by another clinical laboratory, and is reported to have occurred de novo in four individuals with vascular EDS (ClinVar SCV000120504.1; Landrum et al., 2016; Fokkema et al., 2011). Moreover, an abstract by D'hondt et al. (2015) reports that transgenic mice harboring the G183S variant display the clinical features of human vascular EDS, including slow wound healing and thin, translucent skin. The G183S variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The G183S variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. This substitution also affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Pepin et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, four other variants at the same residue (G183C, G183R, G183D, G183A) have each been reported in at least one individual with vascular EDS (Smith et al., 1997; Pepin et al., 2000; Frank et al., 2015; Morissette et al., 2014), supporting the functional importance of this residue of the protein.In summary, G183S in the COL3A1 gene is interpreted as a pathogenic variant. (less)
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Pathogenic
(Aug 10, 2021)
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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:
unknown
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Baylor Genetics
Accession: SCV003835014.1
First in ClinVar: Mar 11, 2023 Last updated: Mar 11, 2023 |
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Pathogenic
(Jan 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001352385.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 12, 2022 |
Comment:
This missense variant changes one of the conserved glycine residues in the repeated Gly-Xaa-Yaa motif of the triple helical region of the COL3A1 protein. This … (more)
This missense variant changes one of the conserved glycine residues in the repeated Gly-Xaa-Yaa motif of the triple helical region of the COL3A1 protein. This variant is also known as G16S in the literature (i.e., the variant alters the 16th glycine of the triple helical region). Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental study with a transgenic Col3a1Tg-G182S mouse line (equivalent to human G183S) has shown that the mice display a phenotype recapitulating characteristics of human vascular Ehlers-Danlos syndrome patients with signs of dermal and vascular fragility (PMID: 29551664). The transgenic mice developed severe transdermal skin wounds, resulting in death at 13-14weeks of age. This variant has been reported in over 25 individuals affected with vascular Ehlers-Danlos syndrome (PMID: 10706896, 18043893, 22065459, 24922459). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Oct 24, 2016)
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criteria provided, single submitter
Method: clinical testing
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Familial thoracic aortic aneurysm and aortic dissection
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002648193.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The p.G183S variant (also known as c.547G>A), located in coding exon 6 of the COL3A1 gene, results from a G to A substitution at nucleotide … (more)
The p.G183S variant (also known as c.547G>A), located in coding exon 6 of the COL3A1 gene, results from a G to A substitution at nucleotide position 547. The glycine at codon 183 is replaced by serine, an amino acid with similar properties. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Schwarze U et al. Am J Hum Genet. 1997;61(6):1276-1286; Pepin MG et al. Genet Med. 2014;16(12):881-8). The p.G183S alteration (sometimes reported with the legacy nomenclature p.G16S) has been detected in many unrelated individuals with Ehlers-Danlos syndrome type IV (vascular type), and cultured skin fibroblasts from a number of these patients have been shown to produce abnormal type III procollagen (Pepin M et al. N. Engl. J. Med. 2000;342:673-80; Kerwin W et al. Int J Cardiovasc Imaging. 2008;24:519-28; Mortani Barbosa EJ et al. Am. J. Med. Genet. A. 2011;155A:3090-4; Pepin MG et al. Genet. Med. 2014;16:881-8). This variant was previously reported in the SNPDatabase as rs121912926, but was absent from population-based cohorts in the Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project databases. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. (less)
Number of individuals with the variant: 1
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Pathogenic
(Sep 25, 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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Invitae
Accession: SCV000631672.7
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
This variant is also known as G16S. This missense change has been observed in individuals with Ehlers-Danlos syndrome IV (PMID: 10706896, 18043893, 24922459). This variant … (more)
This variant is also known as G16S. This missense change has been observed in individuals with Ehlers-Danlos syndrome IV (PMID: 10706896, 18043893, 24922459). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 183 of the COL3A1 protein (p.Gly183Ser). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly183 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9036918, 10706896, 24399159). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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). 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 COL3A1 protein function. ClinVar contains an entry for this variant (Variation ID: 17228). (less)
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Pathogenic
(Mar 09, 2000)
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no assertion criteria provided
Method: literature only
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EHLERS-DANLOS SYNDROME, VASCULAR TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039051.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017 |
Comment on evidence:
In 7 of 135 unrelated families, Pepin et al. (2000) found a gly16-to-ser mutation in the COL3A1 gene as the cause of type IV EDS … (more)
In 7 of 135 unrelated families, Pepin et al. (2000) found a gly16-to-ser mutation in the COL3A1 gene as the cause of type IV EDS (EDSVASC; 130050). (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: SCV000120504.1
First in ClinVar: Mar 13, 2014 Last updated: Mar 13, 2014 |
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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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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 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
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 |
Transforming growth factor-β and inflammation in vascular (type IV) Ehlers-Danlos syndrome. | Morissette R | Circulation. Cardiovascular genetics | 2014 | PMID: 24399159 |
Vascular Ehlers-Danlos syndrome presenting as rapidly progressive multiple arterial aneurysms and dissections. | Mortani Barbosa EJ Jr | American journal of medical genetics. Part A | 2011 | PMID: 22065459 |
Collagen structure and stability. | Shoulders MD | Annual review of biochemistry | 2009 | PMID: 19344236 |
MRI of great vessel morphology and function in Ehlers-Danlos syndrome type IV. | Kerwin W | The international journal of cardiovascular imaging | 2008 | PMID: 18043893 |
Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. | Pepin M | The New England journal of medicine | 2000 | PMID: 10706896 |
Mutations in the COL3A1 gene result in the Ehlers-Danlos syndrome type IV and alterations in the size and distribution of the major collagen fibrils of the dermis. | Smith LT | The Journal of investigative dermatology | 1997 | PMID: 9036918 |
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 |
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Text-mined citations for rs121912926 ...
HelpRecord last updated Feb 28, 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.