rs587779637

Positions:

• chr2-188994288-G-A
• chr2-188994288-G-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1 PM1 PM2 PP2 PP3_Strong PP5_Moderate

The ENST00000304636.9(COL3A1):​c.1249G>A​(p.Gly417Arg) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 ENST00000304636.9 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.15

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 15 ACMG points.

• PS1: Transcript ENST00000304636.9 (COL3A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 940059
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 7 uncertain in ENST00000304636.9
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 2-188994288-G-A is Pathogenic according to our data. Variant chr2-188994288-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101369.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1249G>A	p.Gly417Arg	missense_variant	18/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1249G>A	p.Gly417Arg	missense_variant	18/51	1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.1150G>A	p.Gly384Arg	missense_variant	17/50	1		ENSP00000415346

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 16, 2020	The p.Gly417Arg variant (previously called p.Gly250Arg) in COL3A1 has been reported in at least 1 individual with clinical features of Ehlers-Danlos syndrome type IV (EDS IV, vascular) (Pepin 2000) and was absent from large population studies. 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_Supporting, PM2, PP3. -
Pathogenic, no assertion criteria provided	clinical testing	Collagen Diagnostic Laboratory, University of Washington	-	- -

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	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	4.7	H;H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.92
MutPred		0.99		Gain of methylation at G417 (P = 0.015);Gain of methylation at G417 (P = 0.015);
MVP		1.0
MPC		0.75
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.98
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs587779637; hg19: chr2-189859014;