NM_000090.4:c.1258G>A
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM2PP2PP3_StrongPP5_Very_Strong
The NM_000090.4(COL3A1):c.1258G>A(p.Gly420Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000090.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.1258G>A | p.Gly420Ser | missense_variant | Exon 18 of 51 | 1 | NM_000090.4 | ENSP00000304408.4 | ||
COL3A1 | ENST00000450867.2 | c.1159G>A | p.Gly387Ser | missense_variant | Exon 17 of 50 | 1 | ENSP00000415346.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461454Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727026
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:4
The p.Gly420Ser variant in COL3A1 has been reported in at least 4 individuals with clinical features of Ehlers-Danlos syndrome type IV (EDS IV, vascular; Pepin 2014, Pickup 2011, Wang 2018) and was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 101452). 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 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_Moderate, PM2, PP3. -
This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 420 of the COL3A1 protein (p.Gly420Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with COL3A1-related disease (PMID: 21086191, 21520333, 24922459, 30115950). ClinVar contains an entry for this variant (Variation ID: 101452). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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). For these reasons, this variant has been classified as Pathogenic. -
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Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
The p.G420S pathogenic mutation (also known as c.1258G>A), located in coding exon 18 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1258. The glycine at codon 420 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 detected in multiple individuals with features consistent with COL3A1-related Ehlers-Danlos syndrome (vascular EDS) (Pickup MJ et al. Forensic Sci Med Pathol, 2011 Jun;7:192-7; Wang K et al. J Hum Genet, 2018 Nov;63:1119-1128; Bowen JM et al. Eur J Hum Genet, 2023 Jul;31:749-760; Buso G et al. Vasc Med, 2023 Dec; 1358863X231215330; external communication; Ambry internal data). Internal structural analysis has demonstrated 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
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Connective and Soft Tissue Disorder Pathogenic:1
The patient is heterozygous for the variant. ACMG criteria used: PS4, PM1, PP3 -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain and replaces the glycine in the canonical Gly-X-Y repeat; missense substitution of a canonical glycine residue is expected to disrupt normal protein folding and function, and this is an established mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 21086191, 24922459, 8218237, 33726816, 31447099, 38102934, 30115950, 36977837, 35943490) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at