rs587779433

chr2-188998683-G-Achr2-188998683-G-C

Variant summary

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

The NM_000090.4(COL3A1):c.1987G>A(p.Gly663Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G663D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.56

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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 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 chr2-188998684-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, COL3A1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 2-188998683-G-A is Pathogenic according to our data. Variant chr2-188998683-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519597.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.1987G>A	p.Gly663Ser	missense_variant	29/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.1987G>A	p.Gly663Ser	missense_variant	29/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1888G>A	p.Gly630Ser	missense_variant	28/50	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2022

The p.G663S variant (also known as c.1987G>A), located in coding exon 29 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1987. The glycine at codon 663 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). 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). Alternate amino acid substitutions at this position, p.G663R, p.G663D, and p.G663V, have been described in vascular Ehlers-Danlos syndrome (vEDS) cohorts (Kerwin W et al. Int J Cardiovasc Imaging. 2008;24:519-28; Nakamura M et al. J Cardiol. 2009;53:458-62; Pepin MG et al. Genet Med. 2014;16(12):881-8). 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Ehlers-Danlos syndrome, type 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 15, 2023

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 663 of the COL3A1 protein (p.Gly663Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 519597). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.8	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		1.0	D;.
Vest4		0.94
MutPred		0.99		Gain of phosphorylation at G663 (P = 0.0048);Gain of phosphorylation at G663 (P = 0.0048);
MVP		0.99
MPC		0.62
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.83
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs587779433; hg19: chr2-189863409;