rs373838193
Variant summary
Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PP2PP3
The NM_000090.4(COL3A1):c.1856C>G(p.Pro619Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,510 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P619L) has been classified as Likely benign.
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: Likely_pathogenic. The variant received 6 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL3A1 | ENST00000304636.9 | c.1856C>G | p.Pro619Arg | missense_variant | Exon 26 of 51 | 1 | NM_000090.4 | ENSP00000304408.4 | ||
COL3A1 | ENST00000450867.2 | c.1757C>G | p.Pro586Arg | missense_variant | Exon 25 of 50 | 1 | ENSP00000415346.2 | |||
COL3A1 | ENST00000713745.1 | c.1703C>G | p.Pro568Arg | missense_variant | Exon 24 of 49 | ENSP00000519049.1 | ||||
COL3A1 | ENST00000713744.1 | c.1856C>G | p.Pro619Arg | missense_variant | Exon 26 of 49 | ENSP00000519048.1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD2 exomes AF: 0.0000119 AC: 3AN: 251170 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461510Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727078 show subpopulations
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
This missense variant replaces proline with arginine at codon 619 of the COL3A1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251170 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at