Submissions for variant NM_000090.4(COL3A1):c.4378G>A (p.Val1460Ile)

gnomAD frequency: 0.00002  dbSNP: rs561556753

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001185758	SCV000738530	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2016-08-15	criteria provided, single submitter	clinical testing	The p.V1460I variant (also known as c.4378G>A), located in coding exon 51 of the COL3A1 gene, results from a G to A substitution at nucleotide position 4378. The valine at codon 1460 is replaced by isoleucine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs561556753. Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (1/106160). This variant was not reported in population based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is poorly conserved in available vertebrate species, and isoleucine is the reference amino acid in other 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 alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001185758	SCV001352036	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1460 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 not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002531814	SCV003504808	uncertain significance	Ehlers-Danlos syndrome, type 4	2023-12-28	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 1460 of the COL3A1 protein (p.Val1460Ile). This variant is present in population databases (rs561556753, gnomAD 0.007%). 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: 519604). 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.
GeneDx	RCV003328608	SCV004035870	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); Not located in the triple helical region, where the majority of pathogenic missense variants occur (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function
All of Us Research Program, National Institutes of Health	RCV002531814	SCV004828353	uncertain significance	Ehlers-Danlos syndrome, type 4	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 1460 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 not been identified 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.