ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.4451G>A (p.Gly1484Asp)

gnomAD frequency: 0.00003  dbSNP: rs761481937
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200071 SCV000249995 uncertain significance not provided 2017-06-28 criteria provided, single submitter clinical testing p.Gly1484Asp (G1484D) (GGC>GAC): c.4451 G>A in exon 54 of the COL5A2 gene (NM_000393.3) A variant of unknown significance has been identified in the COL5A2 gene. The G1484D variant has not been published as a mutation or been reported as a benign polymorphism to our knowledge. This variant has been previously identified in an individual referred for Marfan/TAAD testing at GeneDx. The G1484D variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G1484D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, missense mutations in nearby residues have not been reported and the G1484D does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of missense mutations occur (Symoens et al., 2012). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-PANCARD,TAADV2-1.
Ambry Genetics RCV002311047 SCV000320663 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2015-12-16 criteria provided, single submitter clinical testing The p.G1484D variant (also known as c.4451G>A), located in coding exon 54 of the COL5A2 gene, results from a G to A substitution at nucleotide position 4451. The glycine at codon 1484 is replaced by aspartic acid, an amino acid with similar properties. Based on data from ExAC, the A allele was reported in 2 of 121176 (0.002%) total alleles (Exome Aggregation Consortium (ExAC), Cambridge, MA (URL: http://exac.broadinstitute.org) [Accessed December 15, 2015]). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), 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; however, A is the reference nucleotide in six 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.
Invitae RCV002229098 SCV000631608 uncertain significance Ehlers-Danlos syndrome, classic type, 1 2023-08-20 criteria provided, single submitter clinical testing 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 COL5A2 protein function. ClinVar contains an entry for this variant (Variation ID: 213132). This missense change has been observed in individual(s) with clinical features of Ehlers-Danlos syndrome (PMID: 30919572). This variant is present in population databases (rs761481937, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1484 of the COL5A2 protein (p.Gly1484Asp).

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.