2-189008117-G-A

Variant names:

• chr2-189008117-G-A
• rs587779578
• NM_000090.4:c.3500G>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.3500G>A​(p.Gly1167Asp) 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. G1167V) 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: 10.0
• 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)

ENSG00000295704 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr2-189008117-G-T is described in CliVar as Pathogenic. Clinvar id is 101289.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 2-189008117-G-A is Pathogenic according to our data. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189008117-G-A is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 459787.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.3500G>A	p.Gly1167Asp	missense_variant	Exon 47 of 51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.3500G>A	p.Gly1167Asp	missense_variant	Exon 47 of 51	1	NM_000090.4	ENSP00000304408.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jan 03, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with aspartic acid at codon 1167 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it is expected to have deleterious impact on protein structure and function. This variant has been observed in an individual affected with Ehlers-Danlos syndrome (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Likely Pathogenic. -

Ehlers-Danlos syndrome, type 4 Pathogenic:1

Oct 13, 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 aspartic acid, which is acidic and polar, at codon 1167 of the COL3A1 protein (p.Gly1167Asp). 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: 459787). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.3	H;.
PhyloP100		10
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.0	D;D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.99		Loss of relative solvent accessibility (P = 0.0071);.;
MVP		0.98
MPC		0.27
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.99
gMVP		1.0
Mutation Taster		=0/100	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: rs587779578; hg19: chr2-189872843;