ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1787G>A (p.Arg596Gln)

gnomAD frequency: 0.00003  dbSNP: rs774632188
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000772938 SCV000906320 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-03-15 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 596 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with COL3A1-related disorders in the literature. This variant has been identified in 5/282752 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.
CeGaT Center for Human Genetics Tuebingen RCV000997615 SCV001153221 uncertain significance not provided 2022-06-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001063157 SCV001227992 uncertain significance Ehlers-Danlos syndrome, type 4 2023-08-25 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 596 of the COL3A1 protein (p.Arg596Gln). This variant is present in population databases (rs774632188, gnomAD 0.004%). 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. 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. ClinVar contains an entry for this variant (Variation ID: 628468). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions.
GeneDx RCV000997615 SCV001804437 uncertain significance not provided 2023-08-16 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 (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; 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 (HGMD)
Mayo Clinic Laboratories, Mayo Clinic RCV000997615 SCV002541996 uncertain significance not provided 2022-09-15 criteria provided, single submitter clinical testing PP2
Ambry Genetics RCV000772938 SCV002716076 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2024-05-23 criteria provided, single submitter clinical testing The p.R596Q variant (also known as c.1787G>A), located in coding exon 25 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1787. The arginine at codon 596 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is well 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.
All of Us Research Program, National Institutes of Health RCV001063157 SCV004824847 uncertain significance Ehlers-Danlos syndrome, type 4 2023-08-23 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 596 of the COL3A1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 5/282752 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.

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