2-188999569-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000090.4(COL3A1):c.2221G>T(p.Gly741Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G741S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

COL3A1
NM_000090.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.95

Publications

4 publications found

Variant links:

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)

COL3A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 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 chr2-188999569-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 101444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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, 0.995

PP5

Variant 2-188999569-G-T is Pathogenic according to our data. Variant chr2-188999569-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 429978.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 link	c.2221G>T	p.Gly741Cys	missense_variant	Exon 31 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
COL3A1	ENST00000304636.9 link	c.2221G>T	p.Gly741Cys	missense_variant	Exon 31 of 51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2 link	c.2122G>T	p.Gly708Cys	missense_variant	Exon 30 of 50	1		ENSP00000415346.2
COL3A1	ENST00000713745.1 link	c.2068G>T	p.Gly690Cys	missense_variant	Exon 29 of 49			ENSP00000519049.1
COL3A1	ENST00000713744.1 link	c.2221G>T	p.Gly741Cys	missense_variant	Exon 31 of 49			ENSP00000519048.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Pathogenic:1

Aug 30, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G741C pathogenic mutation (also known as c.2221G>T), located in coding exon 31 of the COL3A1 gene, results from a G to T substitution at nucleotide position 2221. The glycine at codon 741 is replaced by cysteine, an amino acid with highly dissimilar 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;16:881-8; Frank M et al. Eur J Hum Genet. 2015;23:1657-64). This particular glycine substitution has been reported in an individual with Ehlers-Danlos syndrome type IV (vascular type), and dermal fibroblasts from that individual have been shown to secrete reduced amounts of COL3A1 (Inokuchi R et al. Medicine (Baltimore). 2014;93:e291). Internal structural analysis has demonstrated 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). In addition, two alterations in the same codon, p.G741S and p.G741D, have also been associated with Ehlers-Danlos syndrome (Morissette R et al. Circ Cardiovasc Genet. 2014;7:80-8; Frank M et al. Eur. J. Hum. Genet. 2015;23:1657-64). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided

Pathogenic:1

May 11, 2017

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The G741C pathogenic variant in the COL3A1 gene has been previously reported in one individual diagnosed with vascular Ehlers-Danlos syndrome (vEDS, EDS IV) (Inokuchi et al., 2014). Additionally, Inokuchi et al. (2014) analyzed cultured fibroblasts from this patient which revealed a significant reduction in the secretion of the alpha-1 chain of type III collagen. The G741C variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G741C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs within the triple helical region of the COL3A1 gene at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the G741C variant 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; Symoens et al., 2012). Substitution of the triplet glycine residue is a well-established pathogenic mechanism for vEDS (Pepin et al., 2015), as further supported by the report of several other triplet glycine substitutions in this region (G726R, G726E, G729R, G729E, G732R, G732V, G735R, G738C, G738S, G738V, G744V, G744A, G744E) in association with vEDS (Stenson et al., 2014). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.91

D;.

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

1.0

D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.2

H;H

PhyloP100

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.8

D;D

REVEL

Pathogenic

1.0

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

1.0

Loss of relative solvent accessibility (P = 0.008);Loss of relative solvent accessibility (P = 0.008);

MVP

0.99

MPC

0.67

ClinPred

1.0

GERP RS

5.3

Varity_R

0.94

gMVP

1.0

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over