ClinVar Genomic variation as it relates to human health
NM_000090.4(COL3A1):c.1744G>A (p.Gly582Ser)
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
-
NM_000090.4(COL3A1):c.1744G>A (p.Gly582Ser)
Variation ID: 17225 Accession: VCV000017225.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 2q32.2 2: 188996479 (GRCh38) [ NCBI UCSC ] 2: 189861205 (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 Mar 13, 2014 May 12, 2024 Dec 14, 2023 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000090.4:c.1744G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000081.2:p.Gly582Ser missense NC_000002.12:g.188996479G>A NC_000002.11:g.189861205G>A NG_007404.1:g.27107G>A LRG_3:g.27107G>A LRG_3t1:c.1744G>A LRG_3p1:p.Gly582Ser P02461:p.Gly582Ser NP_000081.1:p.Gly582Ser - Protein change
- Other names
- G415S
- p.G582S:GGT>AGT
- Canonical SPDI
- NC_000002.12:188996478: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.
-
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. |
|||
COL3A1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
3009 | 3135 |
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 (5) |
criteria provided, multiple submitters, no conflicts
|
Dec 14, 2023 | RCV000018765.41 | |
Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2022 | RCV000181088.18 | |
Pathogenic (1) |
no assertion criteria provided
|
- | RCV000616909.2 | |
Pathogenic (1) |
criteria provided, single submitter
|
Jul 28, 2023 | RCV004528122.1 |
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. |
|
---|---|---|---|---|---|
Pathogenic
(Jul 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
COL3A1-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004111005.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The COL3A1 c.1744G>A variant is predicted to result in the amino acid substitution p.Gly582Ser. This variant was reported in individuals with Ehlers-Danlos syndrome IV (vascular … (more)
The COL3A1 c.1744G>A variant is predicted to result in the amino acid substitution p.Gly582Ser. This variant was reported in individuals with Ehlers-Danlos syndrome IV (vascular type) (Anderson et al. 1997. PubMed ID: 8990011, reported as p.Gly415Ser; Legrand et al. 2018. PubMed ID: 30474650; Henneton et al. 2019. PubMed ID: 30919682; Pepin et al. 2000. PubMed ID: 10706896, reported as Gly415Ser). This variant was also reported as pathogenic in another patient with aneurysm (Weerakkody et al. 2018. PubMed ID: 29543232). In addition, a different variant affecting the same amino acid residue (p.Gly582SArg) was reported to be pathogenic for Ehlers-Danlos Syndrome (Kerwin et al. 2008. PubMed ID: 18043893). This variant impacts a glycine residue of the highly conserved collagen triple helical domain (Gly-X-Y) where Gly substitutions are expected to be pathogenic. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
Pathogenic
(Jun 26, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, type 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004832545.1
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 serine at codon 582 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the … (more)
This missense variant replaces glycine with serine at codon 582 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 several individuals affected with vascular Ehlers-Danlos syndrome (PMID: 24922459, 25758994, 30793832), and in an individual affected with thoracic aortic aneurysm and dissection (PMID: 29543232). 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 Pathogenic. (less)
Number of individuals with the variant: 1
|
|
Pathogenic
(Apr 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, type 4
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004847708.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Gly582Ser variant in COL3A1 has been identified in at least 7 individuals with vascular Ehlers Danlos syndrome (vEDS) and one individual with thoracic arotic … (more)
The p.Gly582Ser variant in COL3A1 has been identified in at least 7 individuals with vascular Ehlers Danlos syndrome (vEDS) and one individual with thoracic arotic aneurysm and dissection (TAAD) (Anderson 1997; Frank 2015, Pepin 2010, Pepin 2014, Weerakkody 2018, Shalhub 2019). In vitro studies provide some evidence that this variant impacts protein function (Anderson 1997). It was also absent from large population studies. In addition, 2 other variants at the same position (p.Gly584Cys and p.Gly582Arg) have also been identified in individuals with vEDS, suggesting that changes at this position are not tolerated. Furthermore, this variant affects the conserved glycine (Gly) residue of the Gly-X-Y repeat region in the triple helical collagen domain, which is a common finding in individuals with vEDS. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant vascular Ehlers Danlos syndrome. ACMG/AMP Criteria applied: PM1; PM2; PP3; PS4_Strong, PS3_Supporting. (less)
|
|
Pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV002563645.11
First in ClinVar: Aug 23, 2022 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
|
|
Pathogenic
(Dec 13, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000233364.11
First in ClinVar: Jul 05, 2015 Last updated: Apr 17, 2019 |
Comment:
The G582S variant in the COL3A1 gene has been reported previously in association with EDS type IV (Anderson et al., 1997; Pepin et al., 2000). … (more)
The G582S variant in the COL3A1 gene has been reported previously in association with EDS type IV (Anderson et al., 1997; Pepin et al., 2000). The G582S variant (also described as G415S due to alternative nomenclature) was initially identified in a 28-year-old female with thin skin, arachnodactyly, a history of multiple aneurysms and vascular ruptures and decreased thermal stability of type III procollagen by in vitro studies (Anderson et al., 1997). The G582S variant was subsequently identified in two additional individuals noted to have arterial complications from EDS type IV (Pepin et al., 2000). This variant is a nonconservative amino acid substitution of a non-polar Glycine with a neutral, polar Serine at a residue that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The G582S variant was not observed in approximately 6,000 individuals of European and African American ancestry by the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. (less)
|
|
Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Ehlers-Danlos syndrome, type 4
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001221066.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 582 of the COL3A1 protein (p.Gly582Ser). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 582 of the COL3A1 protein (p.Gly582Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with vascular Ehlers-Danlos syndrome (PMID: 8990011, 10706896, 29543232, 30793832, 30919682). This variant is also known as p.Gly415Ser. ClinVar contains an entry for this variant (Variation ID: 17225). 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 with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
Likely pathogenic
(Aug 15, 2011)
|
no assertion criteria provided
Method: clinical testing
|
Not provided
Affected status: not provided
Allele origin:
germline
|
Stanford Center for Inherited Cardiovascular Disease, Stanford University
Accession: SCV000280066.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
Comment:
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case … (more)
Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below we would classify this variant as a likely pathogenic variant. Variants that alter the sequence in the triple-helical domain of the COL3A1 gene result in EDS type IV (Schwarze, 2001). Two-thirds of identified disease-causing variants for EDS type IV result in single amino acid substitutions for glycine in the GLY-X-Y repeat of the triple helical region of the type III collagen molecule (GeneReviews). This p.Gly582Ser variant occurs in one of the triple helical region in which variants are known to cause EDS type IV. For example, Anderson et al (1997) reported a glycine to serine substitution at residue 415 in the triple helical region in a 28-year-old woman with thin skin, arachnodactyly, and a history of vascular ruptures. They concluded that this mutation causes a severe form of EDS type IV with multiple aneurisms and vascular ruptures. Pepin et al (2000) identified the underlying COL3A1 mutation in 135 patients with EDS type IV. In 85 of these patients, 73 different point mutations led to the substitution of some other amino acid for glycine throughout the triple-helical domain, one of which was the glycine to serine substitution at residue 415. Furthermore, they noted that this variant had been identified multiple times in unrelated index patients. Additionally, no control data is available. The variant is not in dbSNP or 1000 genomes (as of 25 May 2011). (less)
Number of individuals with the variant: 4
|
|
Pathogenic
(Mar 09, 2000)
|
no assertion criteria provided
Method: literature only
|
EHLERS-DANLOS SYNDROME, VASCULAR TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000039048.3
First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017 |
Comment on evidence:
Anderson et al. (1997) stated that more than 40 mutations in the type III procollagen gene had been described in patients with EDS IV (EDSVASC; … (more)
Anderson et al. (1997) stated that more than 40 mutations in the type III procollagen gene had been described in patients with EDS IV (EDSVASC; 130050). These mutations included missense mutations, splice site mutations, and deletions. They reported a G-to-A transition that altered codon 415 from GGT (glycine) to AGT (serine). They stated that the mutation results in impaired secretion and decreased thermal stability type III procollagen. Pepin et al. (2000) found the G415S mutation in 2 of 135 unrelated EDS IV families. (less)
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Ehlers-Danlos syndrome, type 4
Affected status: yes
Allele origin:
germline
|
Collagen Diagnostic Laboratory, University of Washington
Accession: SCV000120449.1
First in ClinVar: Mar 13, 2014 Last updated: Mar 13, 2014 |
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Familial thoracic aortic aneurysm and aortic dissection
Affected status: yes
Allele origin:
unknown
|
Centre for Genomic and Experimental Medicine, University of Edinburgh
Accession: SCV000731209.1
First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
Clinical Features:
Aneurysm (present)
|
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 |
---|---|---|---|---|
Accuracy of Clinical Diagnostic Criteria for Patients With Vascular Ehlers-Danlos Syndrome in a Tertiary Referral Centre. | Henneton P | Circulation. Genomic and precision medicine | 2019 | PMID: 30919682 |
Spontaneous pneumothorax and hemothorax frequently precede the arterial and intestinal complications of vascular Ehlers-Danlos syndrome. | Shalhub S | American journal of medical genetics. Part A | 2019 | PMID: 30793832 |
Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. | Weerakkody R | Genetics in medicine : official journal of the American College of Medical Genetics | 2018 | PMID: 29543232 |
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 |
Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. | Pepin M | The New England journal of medicine | 2000 | PMID: 10706896 |
A glycine (415)-to-serine substitution results in impaired secretion and decreased thermal stability of type III procollagen in a patient with Ehlers-Danlos syndrome type IV. | Anderson DW | Human mutation | 1997 | PMID: 8990011 |
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 rs121912923 ...
HelpRecord last updated May 12, 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.