rs113485686

Variant names:

• chr2-189001554-G-A
• rs113485686
• NM_000090.4:c.2356G>A

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000090.4(COL3A1):​c.2356G>A​(p.Gly786Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G786V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.13
• Publications: 6 publications found

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]

COL3A1 Gene-Disease associations (from GenCC):

• autosomal dominant Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000090.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-189001555-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 101274.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 2-189001554-G-A is Pathogenic according to our data. Variant chr2-189001554-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2356G>A	p.Gly786Arg	missense_variant	Exon 34 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2356G>A	p.Gly786Arg	missense_variant	Exon 34 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.2257G>A	p.Gly753Arg	missense_variant	Exon 33 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.2203G>A	p.Gly735Arg	missense_variant	Exon 32 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.2356G>A	p.Gly786Arg	missense_variant	Exon 34 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000488 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:4

-

Collagen Diagnostic Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 26, 2025

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 arginine, which is basic and polar, at codon 786 of the COL3A1 protein (p.Gly786Arg). 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: 2243125, 18043893, 24399159, 24650746, 30474650, 31126764). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly619Arg. ClinVar contains an entry for this variant (Variation ID: 17200). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Nov 01, 1991

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2356G>A (p.Gly786Arg) variant in COL3A1 gene that encodes for collagen type III alpha 1 chain, has been reported in at least eight individuals affected with vascular Ehlers-Danlos syndrome (vEDS) or other COL3A1-related phenotypes (PMID: 18043893, 24399159, 24650746, 30474650, 31126764, 36189931, 36977837, 37655064). This variant affects a conserved glycine residue changes to which are significantly enriched in individuals with COL3A1-related conditions (PMID: 24922459, 25758994). Glycine residues within the Gly-X-Y repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). Computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.995). This variant is absent in the general population database gnomAD (v4.1.0), and interpreted as likely pathogenic/pathogenic by multiple submitters in ClinVar database (ClinVar ID: 17200). Another variant affecting the same amino acid residue, p.Gly786Val has been reported in two individuals with vEDS (PMID: 30474650) and classified as pathogenic by single submitter in ClinVar (ID: 101274). Therefore, the c.2356G>A (p.Gly786Arg) variant in COL3A1 gene is classified as likely pathogenic. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Sep 12, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G786R pathogenic mutation (also known as c.2356G>A), located in coding exon 34 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2356. The glycine at codon 786 is replaced by arginine, an amino acid with dissimilar 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 (also known as legacy p.G619R) has been reported in individuals with vascular Ehlers-Danlos syndrome (vEDS), as well as in affected family members (Kontusaari S et al. J. Clin. Invest., 1990 Nov;86:1465-73; Kuivaniemi H et al. J. Clin. Invest., 1991 Nov;88:1441-4; Pepin MG et al. Genet. Med., 2014 Dec;16:881-8; Morissette R et al. Circ Cardiovasc Genet, 2014 Feb;7:80-8). 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). An alternate amino acid substitution at this codon, p.G786V, has also been detected in vEDS cohorts (Pepin MG et al. Genet. Med., 2014 Dec;16:881-8; Henneton P et al. Circ Genom Precis Med, 2019 Mar;12:e001996). 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. -

Nov 05, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 deleterious impact on protein structure and function. This variant has been reported in multiple unrelated individuals affected with vascular Ehlers Danlos syndrome (PMID: 18043893, 24399159, 24650746, 30474650, 31126764, 36977837, 37068529, 37655064). It has been shown that this variant segregates with disease in multiple affected individuals in one family (PMID: 36977837). This variant has also been reported in multiple individuals in one family affected with aortic aneurysm (PMID: 2243125). 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:2

Mar 04, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; 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); Also known as p.(G619R); This variant is associated with the following publications: (PMID: 18043893, 25525159, 2243125, 30474650, 31126764, 24650746, 24399159, 9036918, 10706896) -

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.2	H;H
PhyloP100		8.1
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		1.0		Gain of methylation at G786 (P = 0.0267);Gain of methylation at G786 (P = 0.0267);
MVP		1.0
MPC		0.75
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.85
gMVP		1.0
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs113485686; hg19: chr2-189866280;