rs587779705

Variant names:

• chr2-188990316-G-A
• rs587779705
• NM_000090.4:c.754G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-188990316-G-A
• chr2-188990316-G-C
• chr2-188990316-G-T

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.754G>A​(p.Gly252Ser) 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. G252R) 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:2
• Conservation: PhyloP100: 9.60
• Publications: 0 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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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 chr2-188990316-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 101470.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, 0.994
• PP5: Variant 2-188990316-G-A is Pathogenic according to our data. Variant chr2-188990316-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2120816.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.754G>A	p.Gly252Ser	missense_variant	Exon 10 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.754G>A	p.Gly252Ser	missense_variant	Exon 10 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.754G>A	p.Gly252Ser	missense_variant	Exon 10 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.754G>A	p.Gly252Ser	missense_variant	Exon 10 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.754G>A	p.Gly252Ser	missense_variant	Exon 10 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/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

Sep 18, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G252S variant (also known as c.754G>A), located in coding exon 10 of the COL3A1 gene, results from a G to A substitution at nucleotide position 754. The glycine at codon 252 is replaced by serine, an amino acid with similar properties. The majority (approximately two-thirds) ofCOL3A1mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (PepinMG et al.GenetMed.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 theCOL3A1protein and inserts a bulky side chain into asterically-constrainedregion (Bella J et al.Science.1994;266:75-81;HohenesterE et al.Proc. Natl.Acad. Sci. U.S.A.2008;105:18273-7; Ambry internal data). This alteration has been reported in individuals with concerns for vascular Ehlers-Danlos syndrome (EDS) (Yamaguchi T et al. Am J Med Genet A, 2023 Jan;191:37-51; Ambry internal data). 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

Apr 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Gly252 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been observed in individuals with COL3A1-related conditions (PMID: 22038052, 30474650), which suggests that this may be a clinically significant amino acid residue. 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). 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. This missense change has been observed in individual(s) with COL3A1-related conditions (Invitae). 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 252 of the COL3A1 protein (p.Gly252Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.1	H;H
PhyloP100		9.6
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		0.90	P;.
Vest4		0.96
MutPred		0.99		Gain of phosphorylation at G252 (P = 0.0092);Gain of phosphorylation at G252 (P = 0.0092);
MVP		0.99
MPC		0.62
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.88
gMVP		0.99
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs587779705; hg19: chr2-189855042;