NM_000090.4(COL3A1):c.2959G>A (p.Gly987Ser) AND Familial thoracic aortic aneurysm and aortic dissection

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 3, 2025
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:: RCV002310655.10

Allele description [Variation Report for NM_000090.4(COL3A1):c.2959G>A (p.Gly987Ser)]

NM_000090.4(COL3A1):c.2959G>A (p.Gly987Ser)

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.2959G>A (p.Gly987Ser)

HGVS:

NC_000002.12:g.189005377G>A
NG_007404.1:g.36005G>A
NM_000090.4:c.2959G>AMANE SELECT
NP_000081.1:p.Gly987Ser
NP_000081.2:p.Gly987Ser
LRG_3t1:c.2959G>A
LRG_3:g.36005G>A
NC_000002.11:g.189870103G>A
NM_000090.3:c.2959G>A

Links:

dbSNP: rs587779583

NCBI 1000 Genomes Browser:

rs587779583

Molecular consequence:

NM_000090.4:c.2959G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial thoracic aortic aneurysm and aortic dissection (TAAD)
Synonyms:: Thoracic aortic aneurysm and aortic dissection; Thoracic aortic aneurysms and dissections
Identifiers:: MONDO: MONDO:0019625; MedGen: C4707243; Orphanet: 91387; OMIM: PS607086

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000319284	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24922459, 25758994, 29778910 Citation Link,
SCV006064773	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 3, 2025)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 7695699, 8218237, 19344236, 24922459, 25758994, 29778910, 30474650, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000319284

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV006064773

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 3, 2025)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

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

Characterization of collagen-like peptides containing interruptions in the repeating Gly-X-Y sequence.

Long CG, Braswell E, Zhu D, Apigo J, Baum J, Brodsky B.

Biochemistry. 1993 Nov 2;32(43):11688-95.

PubMed [citation]

PMID:: 8218237

See all PubMed Citations (8)

Details of each submission

From Ambry Genetics, SCV000319284.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The p.G987S pathogenic mutation (also known as c.2959G>A), located in coding exon 41 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2959. The glycine at codon 987 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 (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). This particular glycine substitution has been detected in two vascular Ehlers-Danlos syndrome (EDS) cohorts and has been reported as a likely de novo alteration in a patient with features consistent with EDS (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64; Lan NSR et al. Cardiovasc. Pathol. 2018;35:48-51). Internal structural analysis has demonstrated that this alteration disrupts the characteristic G-X-Y motif in the COL3A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV006064773.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This missense variant replaces glycine with serine at codon 987 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. Although functional studies have not been reported for this variant, conserved glycine residues within the Gly-Xaa-Yaa repeats are required for the structural stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236) and missense variants occurring at these glycine residues have been associated with disease (PMID: 24922459, 25758994). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function. This variant has been reported in individuals affected with vascular Ehlers Danlos syndrome (PMID: 24922459, 25758994, 29778910, 30474650), and has been reported to occur de novo in an affected individual (PMID: 29778910). 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.

#	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: May 16, 2025

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