rs587779584

Variant names:

• chr2-188996134-G-A
• rs587779584
• NM_000090.4:c.1618G>A

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000090.4(COL3A1):​c.1618G>A​(p.Gly540Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,414 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.09
• Publications: 1 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 17 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000090.4
• PM2: Very rare variant in population databases, with high coverage
• 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 2-188996134-G-A is Pathogenic according to our data. Variant chr2-188996134-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 101297.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.1618G>A	p.Gly540Arg	missense_variant	Exon 23 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1618G>A	p.Gly540Arg	missense_variant	Exon 23 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1519G>A	p.Gly507Arg	missense_variant	Exon 22 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713744.1	c.1618G>A	p.Gly540Arg	missense_variant	Exon 23 of 49			ENSP00000519048.1
COL3A1	ENST00000713745.1	c.1608+344G>A		intron_variant	Intron 22 of 48			ENSP00000519049.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461414 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111642

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 30

Alfa AF: 0.000321 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

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

- -

Jun 17, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The COL3A1 c.1618G>A (p.Gly540Arg) variant involves the alteration of a conserved critical nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Other mutations affecting Glycine residues in the Gly-X-Y repeat of the triple helix domain (Gly519Glu, Gly549Glu, Gly567Glu) have been reported in association with EDS, further supporting the functional importance of this region of the protein. This variant is absent in 120568 control chromosomes and has been reported in multiple affected individuals with EDS type IV. In addition, multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jul 07, 2023

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 540 of the COL3A1 protein (p.Gly540Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Ehlers–Danlos syndrome (PMID: 10706896, 24922459, 25355833). This variant is also known as p.Gly373Arg. ClinVar contains an entry for this variant (Variation ID: 101297). 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 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. -

Aug 21, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.99 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 1.00 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000101297 /PMID: 10706896).The variant has been observed in at least two similarly affected unrelated individuals (PMID: 10706896, 24922459, 25355833). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Feb 25, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G540R variant (also known as c.1618G>A), located in coding exon 23 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1618. The glycine at codon 540 is replaced by arginine, an amino acid with dissimilar 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 variant was reported in individual(s) with features consistent with vascular Ehlers-Danlos syndrome (EDS) (Pepin M et al. N Engl J Med, 2000 Mar;342:673-80; Debette S et al. Neurology, 2014 Nov;83:2023-31; Henneton P et al. Circ Genom Precis Med, 2019 Mar;12:e001996; Bowen JM et al. Eur J Hum Genet, 2023 Jul;31:749-760; Shalhub S et al. J Vasc Surg, 2023 Aug;78:394-404; Yagyu T et al. J Am Heart Assoc, 2023 Apr;12:e028625). 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. -

not provided Pathogenic:1

Apr 04, 2022

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); This variant is associated with the following publications: (PMID: 9036918, 24922459, 24399159, 18043893, 25355833, 10706896, 30919682, 30474650, 25758994) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.5	H;H
PhyloP100		9.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.4	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.99		Gain of methylation at G540 (P = 0.0231);Gain of methylation at G540 (P = 0.0231);
MVP		0.99
MPC		0.75
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		1.0
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs587779584; hg19: chr2-189860860; COSMIC: COSV105891954; COSMIC: COSV105891954;