Submissions for variant NM_000090.4(COL3A1):c.923G>A (p.Arg308Gln)

gnomAD frequency: 0.00002  dbSNP: rs753589858

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001187872	SCV001354777	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 308 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 been reported in an individual affected with spontaneous coronary artery dissection (PMID: 36103205). This variant has been identified in 4/251322 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.
GeneDx	RCV001760142	SCV001991331	uncertain significance	not provided	2019-01-24	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat. Although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (Stenson et al., 2014)
Ambry Genetics	RCV001187872	SCV002686807	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2018-02-20	criteria provided, single submitter	clinical testing	The p.R308Q variant (also known as c.923G>A), located in coding exon 13 of the COL3A1 gene, results from a G to A substitution at nucleotide position 923. The arginine at codon 308 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002484026	SCV002786350	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2022-03-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003523075	SCV004301096	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-10-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 308 of the COL3A1 protein (p.Arg308Gln). This variant is present in population databases (rs753589858, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 925744). 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 not expected to disrupt COL3A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV003523075	SCV004833568	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 308 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 been reported in an individual affected with spontaneous coronary artery dissection (PMID: 36103205). This variant has been identified in 4/251322 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.