NM_000090.4(COL3A1):c.3417+1G>A AND Ehlers-Danlos syndrome, type 4

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 26, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000087369.11

Allele description [Variation Report for NM_000090.4(COL3A1):c.3417+1G>A]

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

Gene:

COL3A1:collagen type III alpha 1 chain [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q32.2

Genomic location:

Preferred name:

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

HGVS:

NC_000002.12:g.189007939G>A
NG_007404.1:g.38567G>A
NM_000090.4:c.3417+1G>AMANE SELECT
NP_000081.1:p.Gly1122_Arg1139del+
LRG_3t1:c.3417+1G>A
LRG_3:g.38567G>A
NC_000002.11:g.189872665G>A
NM_000090.3:c.3417+1G>A

Links:

dbSNP: rs587779444

NCBI 1000 Genomes Browser:

rs587779444

Molecular consequence:

NM_000090.4:c.3417+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Name:: Ehlers-Danlos syndrome, type 4
Synonyms:: Ehlers-Danlos syndrome vascular type; Ehlers Danlos syndrome, ecchymotic type; Ehlers Danlos syndrome, arterial type; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0017314; MedGen: C0268338; Orphanet: 286; OMIM: 130050

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000120251	Collagen Diagnostic Laboratory, University of Washington	no assertion criteria provided	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001585876	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 26, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 22019127, 7695699, 8218237, 19344236, 24922459, 25758994, 28492532
SCV003928694	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 25, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24922459, 22019127 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000120251

Collagen Diagnostic Laboratory, University of Washington

no assertion criteria provided

Pathogenic

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001585876

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 26, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV003928694

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Apr 25, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

Pepin M, Schwarze U, Superti-Furga A, Byers PH.

N Engl J Med. 2000 Mar 9;342(10):673-80. Erratum in: N Engl J Med 2001 Feb 1;344(5):392.

PubMed [citation]

PMID:: 10706896

Crystal and molecular structure of a collagen-like peptide at 1.9 A resolution.

Bella J, Eaton M, Brodsky B, Berman HM.

Science. 1994 Oct 7;266(5182):75-81.

PubMed [citation]

PMID:: 7695699

See all PubMed Citations (8)

Details of each submission

From Collagen Diagnostic Laboratory, University of Washington, SCV000120251.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001585876.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003928694.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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