rs587779650

Variant names:

• chr2-188992202-G-A
• rs587779650
• NM_000090.4:c.970G>A

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.970G>A​(p.Gly324Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,720 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G324V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.36
• Publications: 8 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 8 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 chr2-188992203-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1702202.Status of the report is criteria_provided_single_submitter, 1 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 2-188992202-G-A is Pathogenic according to our data. Variant chr2-188992202-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 101388.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.970G>A	p.Gly324Ser	missense_variant	Exon 14 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.970G>A	p.Gly324Ser	missense_variant	Exon 14 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.970G>A	p.Gly324Ser	missense_variant	Exon 14 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713745.1	c.970G>A	p.Gly324Ser	missense_variant	Exon 14 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1	c.970G>A	p.Gly324Ser	missense_variant	Exon 14 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461720 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727178

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111926

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:8

Aug 07, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.970G>A (p.Gly324Ser) variant in COL3A1 gene that encodes for collagen type III alpha 1 chain, has been reported in several individuals (>10) affected with vascular Ehlers-Danlos syndrome or other COL3A1 related phenotypes (PMID: 22713205, 23234825, 25758994, 31008308, 30474650, 31126764, 31903434, 31791984, 35699227, 36977837, 37042257). This variant affects the conserved glycine residue and changes to this amino acid in COL3A1 protein 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). In-silico computational prediction tools suggest that the p.Gly324Ser variant may have deleterious effect on the protein function (REVEL score: 0.98). This variant is absent in the general population database gnomAD and interpreted as pathogenic by several submitters in ClinVar database (ClinVar ID: 101388). Therefore, the c.970G>A (p.Gly324Ser) variant in COL3A1 is classified as pathogenic. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 02, 2023

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.970G>A (p.Gly324Ser) variant in COL3A1 gene that encodes for collagen type III alpha 1 chain, has been reported in several individuals (>10) affected with vascular Ehlers-Danlos syndrome or other COL3A1 related phenotypes (PMID: 22713205, 23234825, 25758994, 31008308, 30474650, 31126764, 31903434, 31791984, 35699227, 36977837, 37042257). This variant affects the conserved glycine residue and changes to this amino acid in COL3A1 protein 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). In-silico computational prediction tools suggest that the p.Gly324Ser variant may have deleterious effect on the protein function (REVEL score: 0.98). This variant is absent in the general population database gnomAD and interpreted as pathogenic by several submitters in ClinVar database (ClinVar ID: 101388). Therefore, the c.970G>A (p.Gly324Ser) variant in COL3A1 is classified as pathogenic. -

-

Collagen Diagnostic Laboratory, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 20, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL3A1 c.970G>A (p.Gly324Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251412 control chromosomes. c.970G>A has been reported in the literature in multiple individuals affected with Ehlers-Danlos Syndrome, Vascular Type (example: Legrand_2019, Traenka_2019, Frank_2015, Pepin_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: two submitters have classified the variant as pathogenic and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 16, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly324Ser variant in COL3A1 has been reported in at least 6 individuals with clinical features of Ehlers-Danlos syndrome type IV (EDS IV, vascular), and segregated with disease in 1 affected relative; however, 3 carriers of theis variant from 1 family did not display any features of EDSIV, vascular (Pepin 2014, Ellis 2012, Frank 2015, Martin 2006). This variant was absent from large population studies and has also been reported in ClinVar (Variation ID 101388). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Variants in COL3A1 affecting conserved glycine (Gly) residues of the G-X-Y repeat region in the triple helical collagen domain, where this variant is located, are strongly associated with EDS IV (Pepin 2000, Pepin 2014, Frank 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant EDS IV. ACMG/AMP Criteria applied: PM1, PS4, PM2, PP3. -

Jul 30, 2024

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 serine, which is neutral and polar, at codon 324 of the COL3A1 protein (p.Gly324Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Ehlers-Danlos syndrome, vascular type (PMID: 17053184, 22713205, 23234825, 25758994). ClinVar contains an entry for this variant (Variation ID: 101388). 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). For these reasons, this variant has been classified as Pathogenic. -

Feb 07, 2024

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: 0.98 (>=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: VCV000101388 /PMID: 17053184).The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22713205, 23234825, 25758994).Different missense changes at the same codon (p.Gly324Asp, p.Gly324Val) have been reported to be associated with COL3A1-related disorder (ClinVar ID: VCV001702202 /PMID: 29907982). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

May 02, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G324S variant (also known as c.970G>A), located in coding exon 14 of the COL3A1 gene, results from a G to A substitution at nucleotide position 970 within the triple-helical domain of COL3A1. The glycine at codon 324 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 Dec;16(12):881-8). This particular alteration has been reported in association with vascular Ehlers-Danlos syndrome (vEDS) in a number of individuals (Martin JJ et al. Stroke 2006 Dec;37(12):2924-9; Rebelo M et al. Acta Med Port. 2011; 24(6):1079-86; Ellis RJ et al. BMJ Case Rep. 2012;doi:10.1136/bcr-2012-007435; Pepin MG et al. Genet. Med. 2014 Dec;16:881-8; Frank M et al. Eur. J. Hum. Genet. 2015 Dec;23:1657-64). This alteration has also been reported in affected individuals in a family with cervical artery dissections (Grond-Ginsbach C et al. Euro. Stroke J. 2017 Jun; 2:137-143). 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

Jul 07, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed 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: 23234825, 24922459, 22713205, 31791984, 31008308, 31903434, 30474650, 17053184, 25758994, 31126764) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.9	H;H
PhyloP100		9.4
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.99		Gain of phosphorylation at G324 (P = 0.0094);Gain of phosphorylation at G324 (P = 0.0094);
MVP		0.99
MPC		0.62
ClinPred		1.0	D
GERP RS		6.1
Varity_R		0.97
gMVP		0.99
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs587779650; hg19: chr2-189856928; COSMIC: COSV58595089; COSMIC: COSV58595089;