ClinVar Genomic variation as it relates to human health
NM_000090.4(COL3A1):c.582+5G>A
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.582+5G>A
Variation ID: 101425 Accession: VCV000101425.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q32.2 2: 188988139 (GRCh38) [ NCBI UCSC ] 2: 189852865 (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 14, 2024 Dec 8, 2020 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000090.4:c.582+5G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NC_000002.12:g.188988139G>A NC_000002.11:g.189852865G>A NG_007404.1:g.18767G>A LRG_3:g.18767G>A LRG_3t1:c.582+5G>A LRG_3p1:p.Gly177_Pro194del NP_000081.1:p.Gly177_Pro194del - Protein change
- Other names
- IVS8DS, G-A, +5
- Canonical SPDI
- NC_000002.12:188988138: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 |
2816 | 2950 |
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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Likely pathogenic (3) |
criteria provided, single submitter
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Aug 17, 2018 | RCV000087663.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 26, 2018 | RCV000788733.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2020 | RCV002354287.1 |
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
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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
(Sep 26, 2018)
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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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Blueprint Genetics
Accession: SCV000927954.1
First in ClinVar: Jul 25, 2019 Last updated: Jul 25, 2019 |
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Pathogenic
(Dec 08, 2020)
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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: SCV002653457.1
First in ClinVar: Nov 29, 2022 Last updated: Nov 29, 2022 |
Comment:
The c.582+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 6 in the COL3A1 gene. This mutation has … (more)
The c.582+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 6 in the COL3A1 gene. This mutation has been reported in individuals with vascular Ehlers-Danlos syndrome (vEDS), including one reportedly de novo case (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Frank M et al. Eur J Hum Genet, 2015 Dec;23:1657-64; Legrand A et al. Genet Med, 2019 07;21:1568-1575). Additional intronic variants predicted to impact this donor site have also been reported in vEDS cohorts, including c.582+2dupT, c.582+5G>A, c.582+6T>A, and c.582+6T>C; exon 6 skipping was confirmed for the c.582+6T>C variant (Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Lloyd J et al. J Med Genet, 1993 May;30:376-80). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Likely pathogenic
(Aug 17, 2018)
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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: SCV000937299.4
First in ClinVar: Aug 14, 2019 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in several individuals affected with Ehlers-Danlos syndrome, vascular type (PMID: 24922459, 25758994, Invitae). ClinVar contains an entry for this variant (Variation ID: 101425). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 6 of the COL3A1 gene. It does not directly change the encoded amino acid sequence of the COL3A1 protein, but it affects a nucleotide within the consensus splice site of the intron. (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: SCV000120555.1
First in ClinVar: Mar 13, 2014 Last updated: Mar 13, 2014 |
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Pathogenic
(Aug 03, 2000)
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no assertion criteria provided
Method: literature only
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EHLERS-DANLOS SYNDROME, VASCULAR TYPE, VARIANT
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000039053.5
First in ClinVar: Apr 04, 2013 Last updated: Dec 26, 2017 |
Comment on evidence:
Pinto et al. (2000) described a splice site mutation in the COL3A1 gene (IVS8+5G-A) in a 40-year-old man who did not show the classic phenotype … (more)
Pinto et al. (2000) described a splice site mutation in the COL3A1 gene (IVS8+5G-A) in a 40-year-old man who did not show the classic phenotype of EDS IV (EDSVASC; 130050). He had no skin or joint abnormalities. Examination showed necrotic degeneration in vascular walls, aneurysms, and medial degeneration in several tissues. Another notable feature was the finding of a normal collagen profile on electrophoresis, despite the DNA abnormality. The patient had a history of bilateral renal-artery stenosis and spontaneous hematothorax. Laparotomy for possible appendicitis revealed a pulseless ileocolic artery and an ischemic colon. Resection of ischemic intestine was performed on 2 successive days; on the third day laparotomy revealed a ruptured abdominal aorta (from which the patient ultimately died) and 6 days later laparotomy revealed a ruptured gallbladder. Byers et al. (2000) stated that their series of patients with EDS IV included 2 with the IVS8+5G-A mutation. (less)
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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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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 |
Frequency of de novo variants and parental mosaicism in vascular Ehlers-Danlos syndrome. | Legrand A | Genetics in medicine : official journal of the American College of Medical Genetics | 2019 | PMID: 30474650 |
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 |
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization. | Buratti E | Nucleic acids research | 2007 | PMID: 17576681 |
Ehlers-Danlos syndrome type IV. | Pinto YM | The New England journal of medicine | 2000 | PMID: 10928898 |
Statistical features of human exons and their flanking regions. | Zhang MQ | Human molecular genetics | 1998 | PMID: 9536098 |
Byers, P. H. Personal Communication. 1998. Seattle, Wash. | - | - | - | - |
Text-mined citations for rs587779671 ...
HelpRecord last updated Feb 20, 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.