rs587779427
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3PP5_Moderate
The NM_000090.4(COL3A1):c.800G>T(p.Gly267Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G267S) has been classified as Pathogenic.
Frequency
Consequence
NM_000090.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.800G>T | p.Gly267Val | missense_variant, splice_region_variant | 11/51 | ENST00000304636.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.800G>T | p.Gly267Val | missense_variant, splice_region_variant | 11/51 | 1 | NM_000090.4 | P1 | |
COL3A1 | ENST00000450867.2 | c.800G>T | p.Gly267Val | missense_variant, splice_region_variant | 11/50 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Ehlers-Danlos syndrome, type 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 15, 2017 | 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, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 24922459, 25758994) compared to the general population (ExAC). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic. This variant has been reported in individuals affected with Ehlers–Danlos syndrome (PMID: 19248182, 24922459). This variant is also known as p.Gly200Val in the literature. ClinVar contains an entry for this variant (Variation ID: 101113). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with valine at codon 267 of the COL3A1 protein (p.Gly267Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. - |
Pathogenic, no assertion criteria provided | clinical testing | Collagen Diagnostic Laboratory, University of Washington | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at