Submissions for variant NM_000090.4(COL3A1):c.1585G>A (p.Val529Ile)

gnomAD frequency: 0.00006  dbSNP: rs140257722

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001179324	SCV000738520	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-05-28	criteria provided, single submitter	clinical testing	The p.V529I variant (also known as c.1585G>A), located in coding exon 22 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1585. The valine at codon 529 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690897	SCV000818628	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 529 of the COL3A1 protein (p.Val529Ile). This variant is present in population databases (rs140257722, gnomAD 0.02%). 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: 519599). 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 with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001179324	SCV001343960	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 529 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 14/168850 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	RCV001788301	SCV002031014	uncertain significance	not provided	2024-02-27	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Occurs in the triple helical domain at the X 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 X position is not a common mechanism of disease (HGMD)
Fulgent Genetics, Fulgent Genetics	RCV002483727	SCV002787125	uncertain significance	Ehlers-Danlos syndrome, type 4; Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome	2021-09-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000690897	SCV004824659	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 529 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 cardiovascular disorders in the literature. This variant has been identified in 14/168850 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.