rs121912926

Positions:

• chr2-188988099-G-A
• chr2-188988099-G-C
• chr2-188988099-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The ENST00000304636.9(COL3A1):​c.547G>A​(p.Gly183Ser) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G183A) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 ENST00000304636.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.24

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 19 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000304636.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-188988100-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1457178.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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, 0.993
• PP5: Variant 2-188988099-G-A is Pathogenic according to our data. Variant chr2-188988099-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188988099-G-A is described in Lovd as [Pathogenic]. Variant chr2-188988099-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.547G>A	p.Gly183Ser	missense_variant	6/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.547G>A	p.Gly183Ser	missense_variant	6/51	1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.547G>A	p.Gly183Ser	missense_variant	6/50	1		ENSP00000415346

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 09, 2000	- -
Pathogenic, no assertion criteria provided	clinical testing	Collagen Diagnostic Laboratory, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 25, 2023	This variant is also known as G16S. This missense change has been observed in individuals with Ehlers-Danlos syndrome IV (PMID: 10706896, 18043893, 24922459). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 183 of the COL3A1 protein (p.Gly183Ser). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly183 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9036918, 10706896, 24399159). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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). 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: 17228). -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 04, 2019	This missense variant changes one of the conserved glycine residues in the repeated Gly-Xaa-Yaa motif of the triple helical region of the COL3A1 protein. This variant is also known as G16S in the literature (i.e., the variant alters the 16th glycine of the triple helical region). Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental study with a transgenic Col3a1Tg-G182S mouse line (equivalent to human G183S) has shown that the mice display a phenotype recapitulating characteristics of human vascular Ehlers-Danlos syndrome patients with signs of dermal and vascular fragility (PMID: 29551664). The transgenic mice developed severe transdermal skin wounds, resulting in death at 13-14weeks of age. This variant has been reported in over 25 individuals affected with vascular Ehlers-Danlos syndrome (PMID: 10706896, 18043893, 22065459, 24922459). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 24, 2016	The p.G183S variant (also known as c.547G>A), located in coding exon 6 of the COL3A1 gene, results from a G to A substitution at nucleotide position 547. The glycine at codon 183 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 (Schwarze U et al. Am J Hum Genet. 1997;61(6):1276-1286; Pepin MG et al. Genet Med. 2014;16(12):881-8). The p.G183S alteration (sometimes reported with the legacy nomenclature p.G16S) has been detected in many unrelated individuals with Ehlers-Danlos syndrome type IV (vascular type), and cultured skin fibroblasts from a number of these patients have been shown to produce abnormal type III procollagen (Pepin M et al. N. Engl. J. Med. 2000;342:673-80; Kerwin W et al. Int J Cardiovasc Imaging. 2008;24:519-28; Mortani Barbosa EJ et al. Am. J. Med. Genet. A. 2011;155A:3090-4; Pepin MG et al. Genet. Med. 2014;16:881-8). This variant was previously reported in the SNPDatabase as rs121912926, but was absent from population-based cohorts in the Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project databases. 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 majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 10, 2017

The G183S pathogenic variant was identified in the COL3A1 gene. G183S, described as G16S in some publications due to alternative nomenclature, was initially reported in seven unrelated families with vascular EDS who experienced both arterial and gastrointestinal complications of the condition (Pepin et al., 2000). Furthermore, cultured fibroblasts from the probands of these families were reported to produce abnormal type III procollagen (Pepin et al., 2000). This pathogenic variant was also reported in two other unrelated individuals with a clinical diagnosis of vascular EDS (Mortani et al., 2011; Frank et al., 2015). In addition, G183S is classified as pathogenic by another clinical laboratory, and is reported to have occurred de novo in four individuals with vascular EDS (ClinVar SCV000120504.1; Landrum et al., 2016; Fokkema et al., 2011). Moreover, an abstract by D'hondt et al. (2015) reports that transgenic mice harboring the G183S variant display the clinical features of human vascular EDS, including slow wound healing and thin, translucent skin. The G183S variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The G183S variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. This substitution also affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Pepin et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, four other variants at the same residue (G183C, G183R, G183D, G183A) have each been reported in at least one individual with vascular EDS (Smith et al., 1997; Pepin et al., 2000; Frank et al., 2015; Morissette et al., 2014), supporting the functional importance of this residue of the protein.In summary, G183S in the COL3A1 gene is interpreted as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.99		Gain of glycosylation at G183 (P = 0);Gain of glycosylation at G183 (P = 0);
MVP		0.99
MPC		0.62
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121912926; hg19: chr2-189852825;