rs397509370
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_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
Consequence
NM_000090.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COL3A1 | ENST00000304636.9 | c.1347+1G>A | splice_donor_variant, intron_variant | Intron 19 of 50 | 1 | NM_000090.4 | ENSP00000304408.4 | |||
| COL3A1 | ENST00000450867.2 | c.1248+1G>A | splice_donor_variant, intron_variant | Intron 18 of 49 | 1 | ENSP00000415346.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:3
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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with Ehlers–Danlos syndrome (PMID: 2349939, 24399159, 24922459, 27306637, 30474650). This variant is also known as G+1 IVS20 and c.1347+1G>A/IVS 19. ClinVar contains an entry for this variant (Variation ID: 17202). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
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. -
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. -
not provided Pathogenic:2
PP1, PP3, PP4, PM2, PS3, PS4_moderate, PVS1_strong -
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) -
COL3A1-related disorder Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at