chr2-188997166-G-A

Position:

• chr2-188997166-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 PP3 PP5_Very_Strong

The NM_000090.4(COL3A1):​c.1763G>A​(p.Gly588Asp) variant causes a missense, splice region 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. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G588S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: COL3A1 NM_000090.4 missense, splice_region
• Scores: Splicing: ADA: 0.9777
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 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 chr2-188997165-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 495541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ 4.0879 (greater than the threshold 3.09). Trascript score misZ 4.5995 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 2-188997166-G-A is Pathogenic according to our data. Variant chr2-188997166-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188997166-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.1763G>A	p.Gly588Asp	missense_variant, splice_region_variant	25/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.1763G>A	p.Gly588Asp	missense_variant, splice_region_variant	25/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1664G>A	p.Gly555Asp	missense_variant, splice_region_variant	24/50	1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 01, 2019	The p.Gly588Asp variant in COL3A1 has been reported in 2 individuals with clinical features of Ehlers-Danlos syndrome type IV (EDS IV; Pepin 2000, Pepin 2014). This variant was absent from large population studies and has been reported as pathogenic in ClinVar (Variation ID 101451). Computational prediction tools and conservation analysis suggest that the p.Gly588Asp variant may impact the protein. 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). Furthermore, a different missense variant affecting the same position, p.Gly588Val, has been reported in an individual with EDS IV (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, PM2, PM5, PP3, PS4_Supporting. -
Pathogenic, no assertion criteria provided	clinical testing	Collagen Diagnostic Laboratory, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 02, 2019	This sequence change replaces glycine with aspartic acid at codon 588 of the COL3A1 protein (p.Gly588Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). This variant has been reported in individuals affected with Ehlers Danlos syndrome type IV (PMID: 10706896, 24922459). ClinVar contains an entry for this variant (Variation ID: 101451). -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 03, 2016

The p.G588D pathogenic mutation (also known as c.1763G>A), located in coding exon 25 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1763. The glycine at codon 588 is replaced by aspartic acid, an amino acid with similar properties. The majority (approximately two-thirds) of COL3A1 variants 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 mutation was identified in two unrelated individuals in a large Ehlers-Danlos syndrome (EDS) type IV cohort, one of whom had biochemically confirmed EDS type IV (Pepin M et al. N. Engl. J. Med. 2000 Mar; 342(10):673-80; Pepin MG et al. Genet. Med. 2014 Dec; 16(12):881-8). Based on the available evidence, p.G588D is interpreted as a disease-causing mutation. -

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	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.4	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.1	D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		1.0		Gain of ubiquitination at K584 (P = 0.1278);Gain of ubiquitination at K584 (P = 0.1278);
MVP		0.99
MPC		0.82
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.98
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.89
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

Publications

LitVar

Other links and lift over

dbSNP: rs587779691; hg19: chr2-189861892;