rs121912926
Variant summary
Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_000090.4(COL3A1):c.547G>A(p.Gly183Ser) 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. 13/22 in silico tools predict a damaging outcome for this variant. 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. G183A) has been classified as Pathogenic.
Frequency
Consequence
NM_000090.4 missense
Scores
Clinical Significance
Conservation
Publications
- autosomal dominant Ehlers-Danlos syndrome, vascular typeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
- Ehlers-Danlos syndrome, vascular typeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- polymicrogyria with or without vascular-type Ehlers-Danlos syndromeInheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 19 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| COL3A1 | ENST00000304636.9 | c.547G>A | p.Gly183Ser | missense_variant | Exon 6 of 51 | 1 | NM_000090.4 | ENSP00000304408.4 | ||
| COL3A1 | ENST00000450867.2 | c.547G>A | p.Gly183Ser | missense_variant | Exon 6 of 50 | 1 | ENSP00000415346.2 | |||
| COL3A1 | ENST00000713745.1 | c.547G>A | p.Gly183Ser | missense_variant | Exon 6 of 49 | ENSP00000519049.1 | ||||
| COL3A1 | ENST00000713744.1 | c.547G>A | p.Gly183Ser | missense_variant | Exon 6 of 49 | ENSP00000519048.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 30
GnomAD4 genome
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:4
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This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 183 of the COL3A1 protein (p.Gly183Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Ehlers-Danlos syndrome IV (PMID: 10706896, 18043893, 24922459). This variant is also known as G16S. ClinVar contains an entry for this variant (Variation ID: 17228). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL3A1 protein function with a positive predictive value of 95%. This variant disrupts the triple helix domain of COL3A1. 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, variants that affect these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). This variant disrupts the p.Gly183 amino acid residue in COL3A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9036918, 10706896, 24399159). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
This missense variant changes one of the conserved glycine residues in the repeated Gly-Xaa-Yaa motif of the triple helical region of the COL3A1 protein. This variant is also known as G16S in the literature (i.e., the variant alters the 16th glycine of the triple helical region). Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. An experimental study with a transgenic Col3a1Tg-G182S mouse line (equivalent to human G183S) has shown that the mice display a phenotype recapitulating characteristics of human vascular Ehlers-Danlos syndrome patients with signs of dermal and vascular fragility (PMID: 29551664). The transgenic mice developed severe transdermal skin wounds, resulting in death at 13-14weeks of age. This variant has been reported in over 25 individuals affected with vascular Ehlers-Danlos syndrome (PMID: 10706896, 18043893, 22065459, 24922459). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on available evidence, this variant is classified as Pathogenic. -
The p.G183S variant (also known as c.547G>A), located in coding exon 6 of the COL3A1 gene, results from a G to A substitution at nucleotide position 547. The glycine at codon 183 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 (Schwarze U et al. Am J Hum Genet. 1997;61(6):1276-1286; Pepin MG et al. Genet Med. 2014;16(12):881-8). The p.G183S alteration (sometimes reported with the legacy nomenclature p.G16S) has been detected in many unrelated individuals with Ehlers-Danlos syndrome type IV (vascular type), and cultured skin fibroblasts from a number of these patients have been shown to produce abnormal type III procollagen (Pepin M et al. N. Engl. J. Med. 2000;342:673-80; Kerwin W et al. Int J Cardiovasc Imaging. 2008;24:519-28; Mortani Barbosa EJ et al. Am. J. Med. Genet. A. 2011;155A:3090-4; Pepin MG et al. Genet. Med. 2014;16:881-8). This variant was previously reported in the SNPDatabase as rs121912926, but was absent from population-based cohorts in the Exome Aggregation Consortium (ExAC), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project databases. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
not provided Pathogenic:1
The G183S pathogenic variant was identified in the COL3A1 gene. G183S, described as G16S in some publications due to alternative nomenclature, was initially reported in seven unrelated families with vascular EDS who experienced both arterial and gastrointestinal complications of the condition (Pepin et al., 2000). Furthermore, cultured fibroblasts from the probands of these families were reported to produce abnormal type III procollagen (Pepin et al., 2000). This pathogenic variant was also reported in two other unrelated individuals with a clinical diagnosis of vascular EDS (Mortani et al., 2011; Frank et al., 2015). In addition, G183S is classified as pathogenic by another clinical laboratory, and is reported to have occurred de novo in four individuals with vascular EDS (ClinVar SCV000120504.1; Landrum et al., 2016; Fokkema et al., 2011). Moreover, an abstract by D'hondt et al. (2015) reports that transgenic mice harboring the G183S variant display the clinical features of human vascular EDS, including slow wound healing and thin, translucent skin. The G183S variant is also not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).The G183S variant is a non-conservative amino acid substitution that occurs at a position that is conserved across species. This substitution also affects a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL3A1 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Pepin et al., 2015). In silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, four other variants at the same residue (G183C, G183R, G183D, G183A) have each been reported in at least one individual with vascular EDS (Smith et al., 1997; Pepin et al., 2000; Frank et al., 2015; Morissette et al., 2014), supporting the functional importance of this residue of the protein.In summary, G183S in the COL3A1 gene is interpreted as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at