rs121912923

Variant names:

• chr2-188996479-G-A
• rs121912923
• NM_000090.4:c.1744G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-188996479-G-A
• chr2-188996479-G-C
• chr2-188996479-G-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000090.4(COL3A1):​c.1744G>A​(p.Gly582Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 9.76

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

ACMG classification

Verdict is Pathogenic. Variant got 15 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the COL3A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 4.0879 (above the threshold of 3.09). Trascript score misZ: 4.5995 (above the threshold of 3.09). GenCC associations: The gene is linked to Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 2-188996479-G-A is Pathogenic according to our data. Variant chr2-188996479-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188996479-G-A is described in Lovd as [Pathogenic]. Variant chr2-188996479-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1744G>A	p.Gly582Ser	missense_variant	Exon 24 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1744G>A	p.Gly582Ser	missense_variant	Exon 24 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1645G>A	p.Gly549Ser	missense_variant	Exon 23 of 50	1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:5

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Collagen Diagnostic Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 17, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 09, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Dec 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 26, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Pathogenic:3

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 31, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect via decreased thermal stability and temperature sensitive secretion of procollagen (PMID: 8990011); Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(G415S); This variant is associated with the following publications: (PMID: 10706896, 24922459, 25758994, 30919682, 30793832, 29543232, 30474650, 38623759, 8990011) -

Aug 15, 2011

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

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Centre for Genomic and Experimental Medicine, University of Edinburgh

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 15, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G582S pathogenic mutation (also known as c.1744G>A), located in coding exon 24 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1744. The glycine at codon 582 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 variant (also referred to as p.G415S) has been detected in individuals with features consistent with vascular Ehlers-Danlos syndrome (Anderson DW et al. Hum Mutat, 1997;9:62-3; Frank M et al. Eur J Hum Genet, 2015 Dec;23:1657-64; Pepin MG et al. Genet Med, 2014 Dec;16:881-8; Weerakkody R et al. Genet Med, 2018 Nov;20:1414-1422; Shalhub S et al. Am J Med Genet A, 2019 May;179:797-802; Demirdas S et al. Circ Genom Precis Med, 2024 Jun;17:e003978). Internal structural analysis indicates 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). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

COL3A1-related disorder Pathogenic:1

Jul 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.8	H;H
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		1.0		Gain of phosphorylation at G582 (P = 0.0101);Gain of phosphorylation at G582 (P = 0.0101);
MVP		1.0
MPC		0.62
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912923; hg19: chr2-189861205;