ClinVar Miner

Submissions for variant NM_000090.3(COL3A1):c.2723C>T (p.Ala908Val) (rs144036995)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000400728 SCV000425533 uncertain significance Ehlers-Danlos syndrome, type 4 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000521444 SCV000620190 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the COL3A1 gene. The A908V variant has not been published as pathogenic in association with vEDS or been reported as benign to our knowledge. The A908V variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A908V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. Nevertheless, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Finally, although the A908V variant occurs within the triple helical region of the COL3A1 gene, it does not affect a Glycine residue in a Gly-X-Y motif, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012).
Invitae RCV000400728 SCV000631648 uncertain significance Ehlers-Danlos syndrome, type 4 2018-09-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 908 of the COL3A1 protein (p.Ala908Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs144036995, ExAC 0.009%). This variant has not been reported in the literature in individuals with a COL3A1-related disease. ClinVar contains an entry for this variant (Variation ID: 333063). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on COL3A1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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