chr2-188994595-G-A

Position:

• chr2-188994595-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000090.4(COL3A1):​c.1347+1G>A variant causes a splice donor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL3A1 NM_000090.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 8.01

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.012042718 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.4, offset of -44, new splice context is: ctgGTaaga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-188994595-G-A is Pathogenic according to our data. Variant chr2-188994595-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188994595-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1347+1G>A		splice_donor_variant, intron_variant		ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1347+1G>A		splice_donor_variant, intron_variant		1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.1248+1G>A		splice_donor_variant, intron_variant		1		ENSP00000415346.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Collagen Diagnostic Laboratory, University of Washington	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1990	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 17202). This variant is also known as G+1 IVS20 and c.1347+1G>A/IVS 19. Disruption of this splice site has been observed in individuals with Ehlers–Danlos syndrome (PMID: 2349939, 24399159, 24922459, 27306637, 30474650). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 19 of the COL3A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL3A1 are known to be pathogenic (PMID: 24922459). -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 06, 2021	This variant causes a G to A nucleotide substitution at the +1 position of intron 19 of the COL3A1 gene. An RNA study has shown that this variant causes complex aberrant splicing due to in-frame skipping of an exon and a use of cryptic splice donor site that leads to in-frame insertion of 24 nucleotides (PMID: 2349939). This variant is a recurrent mutation in individuals affected with vascular Ehlers–Danlos syndrome (PMID: 24399159, 24922459, 27306637, 27462043, 30919682, 31600821). This variant has also been reported in an individual affected with aortic aneurysms that ruptured and resulted in death (PMID: 2349939). A study using fibroblasts from this individual has shown a decrease in pepsin-resistant type Ill procollagen in the cells (PMID: 2349939). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of COL3A1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 23, 2023	The c.1347+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 19 of the COL3A1 gene. This alteration has been reported in association with Ehlers-Danlos syndrome type IV (vascular type) and related features and has also been shown to result in abnormal splicing (Kontusaari S et al. ;Am J Hum Genet. 1990;47(1):112-20; Watanabe A et al. Circ J. 2007;71(2):261-5; Drera B et al. J Dermatol Sci. 2011;64(3):237-40). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); Reported as pathogenic by other clinical laboratories in ClinVar (ClinVar Variant ID# 17202; Landrum et al., 2016); Canonical splice site variant expected to result in aberrant splicing; Multiple functional studies demonstrate that c.1347+1 G>A results in a complex splice outcome that includes skipping of exon 19, retention of intron 19, and use of a cryptic splice donor site that leads to insertion of the first 24 nucleotides of intron 19 (Kontusaari et al., 1990; Anderson et al., 1997); Aberrant splicing is a common mechanism of disease in this gene (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 27306637, 22019127, 2349939, 24922459, 17251678, 21219851, 9143932, 30474650, 27462043, 30919682, 31600821) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2023	PP1, PP3, PP4, PM2, PS3, PS4_moderate, PVS1_strong -

COL3A1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2023

The COL3A1 c.1347+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the heterozygous state in multiple individuals with vascular Ehlers-Danlos syndrome (see for example, Cazzato et al. 2016. PubMed ID: 27306637; Li et al. 2022. PubMed ID: 36119745; reported as G+1 IVS20 in Kontusaari et al. 1990. PubMed ID: 2349939). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Variants that disrupt the consensus splice donor site in COL3A1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		6.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397509370; hg19: chr2-189859321; COSMIC: COSV58587081; COSMIC: COSV58587081;