ClinVar Miner

Submissions for variant NM_000393.5(COL5A2):c.4451G>A (p.Gly1484Asp) (rs761481937)

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Total submissions: 3
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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 RCV000253258 SCV000320663 uncertain significance Cardiovascular phenotype 2015-12-16 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence
Invitae RCV000544611 SCV000631608 uncertain significance Ehlers-Danlos syndrome, classic type 2018-10-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 1484 of the COL5A2 protein (p.Gly1484Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is present in population databases (rs761481937, ExAC 0.006%) but has not been reported in the literature in individuals with a COL5A2-related disease. ClinVar contains an entry for this variant (Variation ID: 213132). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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