rs113485686

Positions:

• chr2-189001554-G-A

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.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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely 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

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 gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ 4.0879 (greater than the threshold 3.09). Trascript score misZ 4.5995 (greater than threshold 3.09). GenCC has associacion of gene with 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, 0.995
• 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. Variant chr2-189001554-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2356G>A	p.Gly786Arg	missense_variant	34/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2356G>A	p.Gly786Arg	missense_variant	34/51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.2257G>A	p.Gly753Arg	missense_variant	33/50	1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00154 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

Pathogenic, no assertion criteria provided	clinical testing	Collagen Diagnostic Laboratory, University of Washington	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1991	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 24, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	For these reasons, this variant has been classified as Pathogenic. 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). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. ClinVar contains an entry for this variant (Variation ID: 17200). This variant is also known as p.Gly619Arg. 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 not present in population databases (gnomAD no frequency). 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). -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 06, 2022	This missense variant replaces glycine with arginine at codon 786 of the COL3A1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it alters one of the conserved glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain (PMID: 7695699, 8218237, 19344236) and is expected to disrupt COL3A1 protein function. This variant has been reported in mutiple individuals affected with vascular Ehlers-Danlos syndrome (PMID: 18043893, 24399159, 24650746, 30474650, 31126764) and in a family with strong history of 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 Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2023	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. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 2024	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -

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
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

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: rs113485686; hg19: chr2-189866280;