rs587779471

Positions:

• chr2-189004090-G-A
• chr2-189004090-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000090.4(COL3A1):​c.2770G>A​(p.Gly924Ser) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.94

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 Likely_pathogenic. Variant got 9 ACMG points.

• 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, 0.995
• PP5: Variant 2-189004090-G-A is Pathogenic according to our data. Variant chr2-189004090-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 101316.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.2770G>A	p.Gly924Ser	missense_variant	39/51	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2770G>A	p.Gly924Ser	missense_variant	39/51	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.2671G>A	p.Gly891Ser	missense_variant	38/50	1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 03, 2021

The p.G924S pathogenic mutation (also known as c.2770G>A), located in coding exon 39 of the COL3A1 gene, results from a G to A substitution at nucleotide position 2770. The glycine at codon 924 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 (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). This particular glycine substitution has been reported in individuals with vascular Ehlers-Danlos syndrome (Ambry internal data; Pepin MG et al. Genet Med, 2014 Dec;16:881-8). Internal structural analysis indicates 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; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Ehlers-Danlos syndrome, type 4 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Collagen Diagnostic Laboratory, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.9	H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	1.0
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.98		Gain of phosphorylation at G924 (P = 0.0039);
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.90
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: rs587779471; hg19: chr2-189868816;