VCV000101132.10 - ClinVar

NM_000090.4(COL3A1):c.3417+1G>A

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

3 out of 4 submissions contributed to this classification

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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000090.4(COL3A1):c.3417+1G>A

Variation ID: 101132 Accession: VCV000101132.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q32.2 2: 189007939 (GRCh38) [ NCBI UCSC ] 2: 189872665 (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	Feb 25, 2025	Dec 26, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000090.4:c.3417+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NC_000002.12:g.189007939G>A
NC_000002.11:g.189872665G>A
NG_007404.1:g.38567G>A
LRG_3:g.38567G>A
LRG_3t1:c.3417+1G>A
	NP_000081.1:p.Gly1122_Arg1139del+

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000002.12:189007938:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Links

dbSNP: rs587779444 ClinGen: CA006363 VarSome

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
Gene	OMIM	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	3351	3484

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.
Ehlers-Danlos syndrome, type 4	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 26, 2023	RCV000087369.11
not provided	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2016	RCV000442138.2

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.
Pathogenic (Apr 25, 2023) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Ehlers-Danlos syndrome, type 4 Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003928694.1 First in ClinVar: Jun 03, 2023 Last updated: Jun 03, 2023	Publications: PubMed (2) PubMed: 24922459‚ 22019127 Comment: Variant summary: COL3A1 c.3417+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: COL3A1 c.3417+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in the in-frame skipping of exon 46 (e.g. PMID:22019127). This is expected to affect the triple-helical region of the encoded protein and alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. The variant was absent in 251444 control chromosomes (gnomAD). c.3417+1G>A has been reported in the literature in individuals affected with Ehlers-Danlos Syndrome, Vascular Type (PMID: 22019127, 24922459). These data indicate that the variant is likely associated with disease. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Dec 13, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: de novo	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000511436.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017
Pathogenic (Dec 26, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Ehlers-Danlos syndrome, type 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001585876.5 First in ClinVar: May 10, 2021 Last updated: Feb 25, 2025	Publications: PubMed (6) PubMed: 22019127‚ 24922459‚ 7695699‚ 8218237‚ 19344236‚ 25758994 Comment: This sequence change affects a donor splice site in intron 46 of the COL3A1 gene. RNA analysis indicates that disruption of this splice site induces … (more) This sequence change affects a donor splice site in intron 46 of the COL3A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Ehlers-Danlos syndrome (PMID: 22019127, 24922459; Invitae). ClinVar contains an entry for this variant (Variation ID: 101132). Studies have shown that disruption of this splice site results in skipping of exon 46, but is expected to preserve the integrity of the reading-frame (PMID: 22019127). 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)
Pathogenic (-) N Not contributing to aggregate classification	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: SCV000120251.1 First in ClinVar: Mar 13, 2014 Last updated: Mar 13, 2014	Publications: PubMed (1) PubMed: 10706896

Comment:

Variant summary: COL3A1 c.3417+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant indeed affects mRNA splicing and results in the in-frame skipping of exon 46 (e.g. PMID:22019127). This is expected to affect the triple-helical region of the encoded protein and alterations of glycine residues within the collagen triple-helix are common mechanisms of disease. The variant was absent in 251444 control chromosomes (gnomAD). c.3417+1G>A has been reported in the literature in individuals affected with Ehlers-Danlos Syndrome, Vascular Type (PMID: 22019127, 24922459). These data indicate that the variant is likely associated with disease. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change affects a donor splice site in intron 46 of the COL3A1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Ehlers-Danlos syndrome (PMID: 22019127, 24922459; Invitae). ClinVar contains an entry for this variant (Variation ID: 101132). Studies have shown that disruption of this splice site results in skipping of exon 46, but is expected to preserve the integrity of the reading-frame (PMID: 22019127). 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.

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:

Citations for germline classification of this variant

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
Diagnosis of vascular Ehlers-Danlos syndrome in Italy: clinical findings and novel COL3A1 mutations.	Drera B	Journal of dermatological science	2011	PMID: 22019127
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
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 rs587779444 ...

These 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 Feb 26, 2025

ClinVar Genomic variation as it relates to human health

NM_000090.4(COL3A1):c.3417+1G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587779444 ...