rs587779578
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The ENST00000304636.9(COL3A1):c.3500G>A(p.Gly1167Asp) 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. 12/21 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. G1167V) has been classified as Pathogenic.
Frequency
Consequence
ENST00000304636.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL3A1 | NM_000090.4 | c.3500G>A | p.Gly1167Asp | missense_variant | 47/51 | ENST00000304636.9 | NP_000081.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.3500G>A | p.Gly1167Asp | missense_variant | 47/51 | 1 | NM_000090.4 | ENSP00000304408 | P1 | |
COL3A1 | ENST00000450867.2 | c.3401G>A | p.Gly1134Asp | missense_variant | 46/50 | 1 | ENSP00000415346 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2022 | This missense variant replaces glycine with aspartic acid at codon 1167 of the COL3A1 protein. This variant changes one of the conserved glycine residues within the Gly-Xaa-Yaa repeat motifs of the triple helical domain of the COL3A1 protein that are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Although functional studies have not been reported for this variant, it is expected to have deleterious impact on protein structure and function. This variant has been observed in an individual affected with Ehlers-Danlos syndrome (Color internal data). 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 Likely Pathogenic. - |
Ehlers-Danlos syndrome, type 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 25, 2017 | For these reasons, this variant has been classified as Pathogenic. Several different missense substitutions at this codon (p.Gly1167Arg, p.Gly1167Val, p.Gly1167Cys) are absent from population databases and have been observed in individuals with Ehlers-Danlos syndrome type IV (PMID: 24650746, 8680408, 24399159). This suggests that the glycine residue is critical for COL3A1 protein function and that other missense substitutions at this position may also be pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL3A1-related disease. This sequence change replaces glycine with aspartic acid at codon 1167 of the COL3A1 protein (p.Gly1167Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at